CN115698024A - Spiro-sulfonamide derivatives as myeloid leukemia 1 (MCL-1) protein inhibitors - Google Patents

Abstract

The present disclosure relates to crystalline forms of compounds of formula I and pharmaceutically acceptable salts thereof. Also described are pharmaceutical compositions comprising compounds of formula I and methods of their use and preparation. Formula I:

Description

Spiro-sulfonamide derivatives as inhibitors of myeloid leukemia 1 (MCL-1) protein biology

Cross References to Related Applications

This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/024,110, filed May 13, 2020, which is incorporated herein by reference in its entirety.

technical field

The present disclosure relates to MCL-1 inhibitors and methods of use thereof.

Background technique

Apoptosis (programmed cell death) is a highly conserved cellular process required for embryonic development and normal tissue homeostasis (Ashkenazi A. et al., Nat. Rev. Drug Discov. 2017, 16, 273-284). Apoptotic cell death involves morphological changes such as nuclear condensation, DNA fragmentation, and biochemical phenomena such as activation of caspases, which cause damage to key structural components of the cell, leading to its disintegration and death. The regulation of the apoptotic process is complex and involves the activation or repression of several intracellular signaling pathways (Cory S. et al., Nature Review Cancer 2002, 2, 647-656; Thomas L.W. et al., FEBS Lett. 2010, 584, 2981- 2989; Adams J.M. et al., Oncogene 2007, 26, 1324-1337).

The Bcl-2 protein family, including proapoptotic and antiapoptotic members, plays a key role in the regulation of the apoptotic process (Youle R.J. et al., Nat. Rev. Mol. Cell Biol. 2008, 9, 47-59; Kelly G.L. et al., Adv. Cancer Res. 2011, 111, 39-96). Bcl-2, Bcl-XL, Bcl-W, Mcl-1 and Al are anti-apoptotic proteins and they share a common BH region. In contrast, pro-apoptotic family members fall into two groups. Multi-domain pro-apoptotic proteins, such as Bax, Bak, and Bok, are generally considered to have BH1-3 domains, whereas BH3-only proteins are considered to have homology only in the BH3 domain. Members of BH3-only proteins include Bad, Bim, Bid, Noxa, Puma, Bik/Blk, Bmf, Hrk/DP5, Beclin-1, and Mule (XuG. et al., Bioorg. Med. Chem. 2017, 25, 5548-5556 ; Hardwick J.M. et al., Cell. 2009, 138, 404; Reed J.C., Cell Death Differ. 2018, 25, 3-6; Kang M.H. et al., Clin Cancer Res 2009, 15, 1126-1132). Pro-apoptotic members such as BAX and BAK form homo-oligomers in the mitochondrial outer membrane upon activation, leading to pore formation and escape of mitochondrial contents, a step that triggers apoptosis. Anti-apoptotic members of the Bcl-2 family (such as Bcl-2, Bel-XL and Mcl-1) block the activity of BAX and BAK. In normal cells, this process is tightly regulated. Abnormal cells can dysregulate this process to avoid cell death. One of the ways cancer cells can achieve this is by upregulating anti-apoptotic members of the Bcl-2 protein family. Overexpression or upregulation of antiapoptotic Bcl-2 family proteins increases cancer cell survival and leads to resistance to multiple anticancer therapies.

Aberrant expression or function of proteins responsible for apoptotic signaling contributes to numerous human pathologies, including autoimmune diseases, neurodegeneration (such as Parkinson's disease, Alzheimer's disease, and ischemia), inflammatory diseases, viral infections, and cancer (such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, etc.) (Hanahan D. et al., Cell 2000, 100.57-70). Here, targeting key apoptosis regulators for cancer therapy is prospective (Kale J. et al., Cell Death Differ. 2018, 25, 65-80; Vogler M. et al., Cell Death Differ. 2009, 16, 360 -367).

By overexpressing one or more of these pro-survival proteins, cancer cells can evade elimination from normal physiological processes and thereby gain a survival advantage. Myeloid leukemia-1 (Mcl-1) is a member of the pro-survival Bcl-2 protein family. Mcl-1 has unique properties that are critical for embryonic development and the survival of all hematopoietic lineage and progenitor cell populations. Mcl-1 is one of the most common genetic aberrations in human cancers and is highly expressed in many tumor types. Mcl-1 overexpression in human cancers is associated with high tumor grade and poor survival (Beroukhim R. et al., Nature 2010, 463, 899-905). Mcl-1 overexpression prevents cancer cells from undergoing programmed cell death (apoptosis), allowing cells to survive widespread genetic damage. Furthermore, its expansion is associated with intrinsic and acquired resistance to a variety of anti-tumorigenic agents, including chemotherapeutics such as microtubule-binding agents, paclitaxel, and gemcitabine, and Apoptosis inducers such as TRAIL, Bcl-2 inhibitors, venetoclax and Bcl-2/Bcl-XL dual inhibitor navitoclax. Not only did gene silencing approaches specifically targeting Mcl-1 bypass this resistance phenotype, but certain cancer cell types frequently undergo cell death in response to Mcl-1 silencing, suggesting a dependence on Mcl-1 for survival. Therefore, methods of inhibiting the function of Mcl-1 have attracted considerable attention for cancer therapy (Wertz I.E et al., Nature 2011, 471, 110-114; Zhang B. et al., Blood 2002, 99, 1885-1893).

Contents of the invention

The present disclosure also relates to N,N-dimethylcarbamate [(3R,6R,7S,8E,22S)-6'-chloro-12,12-dimethyl-13,15,15-trioxo-spiro [11,20-Dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]-pentacosa-8,16,18,24-tetraene-22 , 1'-tetrahydronaphthalene] -7-yl] ester (i.e. the crystalline form of the compound of formula I),

The disclosure also relates to pharmaceutical compositions containing such forms, and also describes methods of using such forms.

The present disclosure also relates to pharmaceutically acceptable salts of said compounds of formula I.

The present disclosure also relates to choline, benzathine, imidazole, piperazine, piperidine, (S)-(-)-α-methylbenzylamine, ethylenediamine, potassium and 4-((2-aminoethylamine) of formula I. base) amino)-4-methylpentan-2-one salt.

Also described are crystalline forms of such salts, as well as pharmaceutical compositions containing such salts and methods of using such salts.

Description of drawings

Figure 1 shows the XRPD of Formula I-Form I.

Figure 2 shows the DSC thermogram of Formula I-Form I.

Figure 3 shows the TGA curve of Formula I-Form I.

4A and 4B show the DVS curves of Formula I-Form I.

Figure 5 shows the XRPD of Formula I-Form I before (top) and after (bottom) DVS.

Figure 6 shows the XRPD of Formula I-Form II.

Figure 7 shows the DSC thermogram of Formula I-Form II.

Figure 8 shows the XRPD of the choline salt of Formula I.

Figure 9 shows the DSC thermogram of the choline salt of Formula I.

Figure 10 shows the TGA curve of the choline salt of Formula I.

Figure 11 shows the NMR spectrum (600 MHz in CDCl ₃ ) of the choline salt of formula I.

Figure 12 shows the XRPD of the benzathine salt of Formula I.

Figure 13 shows the DSC thermogram of the benzathine salt of Formula I.

Figure 14 shows the TGA curve of the benzathine salt of Formula I.

Figure 15 shows the NMR spectrum (600 MHz in CDCl ₃ ) of the benzathine salt of Formula I.

Figure 16 shows the XRPD of the imidazolium salt of Formula I.

Figure 17 shows the DSC thermogram of the imidazolium salt of Formula I.

Figure 18 shows the TGA curves of imidazolium salts of Formula I.

Figure 19 shows the NMR spectrum (600 MHz in CDCl ₃ ) of the imidazolium salt of Formula I.

Figure 20 shows the XRPD of the piperazine salt of Formula I (Form 1).

Figure 20A shows the XRPD of the piperazine salt of Formula I (Form 2)

Figure 20B shows the XRPD of the piperazine salt of Formula I (Form 3)

Figure 21 shows the DSC thermogram of the piperazine salt of Formula I (Form 1).

Figure 21A shows the DSC thermogram of the piperazine salt of Formula I (Form 2).

Figure 22 shows the TGA curve of the piperazine salt of Formula I (Form 1).

Figure 23 shows the NMR spectrum (600 MHz in CDCl ₃ ) of the piperazine salt of Formula I (Form 1).

Figure 24 shows the XRPD of the piperidine salt of Formula I (Form 1).

Figure 24A shows the XRPD of the piperidinium salt of Formula I (Form 2).

Figure 25 shows the DSC thermogram of the piperidinium salt of Formula I (Form 1).

Figure 26 shows the TGA curve of the piperidinium salt of Formula I (Form 1).

Figure 27 shows the NMR spectrum (600 MHz in CDCl ₃ ) of the piperidinium salt of Formula I (Form 1).

Figure 28 shows the XRPD of the potassium salt of Formula I.

Figure 29 shows the DSC thermogram of the potassium salt of Formula I.

Figure 30 shows the XRPD of (S)-(-)-α-methylbenzylamine salt of Formula I.

Figure 31 shows the DSC thermogram of (S)-(-)-α-methylbenzylamine salt of Formula I.

Figure 32 shows the XRPD of the ethylenediamine salt of Formula I (Form 1).

Figure 32A shows the XRPD of the ethylenediamine salt of Formula I (Form 2).

Figure 33 shows the NMR spectrum of the ethylenediamine salt of Formula I (Form 1).

Figure 34 shows the XRPD of 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I.

Figure 35 shows the DSC thermogram of 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I.

Figure 36 shows the TGA curve of 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I.

Figure 37 shows the NMR spectrum (600 MHz in CDCl ₃ ) of 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I.

Detailed ways

The present disclosure can be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods which are, for brevity, described in the context of a single aspect may also be provided separately or in any subcombination.

"Pharmaceutically acceptable" means approved or licensable by a regulatory agency of the Federal or a state government or the equivalent agency in a country other than the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals (e.g., in humans) By.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; Alkyl propanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- Toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid , lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) when the acidic protons present in the parent compound are ions, alkaline earth ions or aluminum ions); or the salts formed when coordinating with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts also include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, non-toxic salts of organic or inorganic acids, such as hydrochloride, Hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

"Pharmaceutically acceptable excipient" means a substance that is non-toxic, biologically tolerable and otherwise biologically suitable for administration to a subject, for example added to a pharmacological composition or otherwise used An inert substance that acts as a vehicle, carrier, or diluent to facilitate the administration of a medicament and is compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

"Solvate" means a physical association of a compound of formula I with one or more solvent molecules.

"Subject" includes humans. The terms "human", "patient" and "subject" are used interchangeably herein.

In one embodiment, "treating" any disease or condition refers to ameliorating the disease or condition (ie, arresting or reducing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" refers to modulating a disease or disorder either physically (eg, stabilization of discernible symptoms), physiologically (eg, stabilization of a bodily parameter), or both. In yet another embodiment, "treating" refers to delaying the onset of a disease or condition.

Where the context permits, "a compound of the present disclosure" and equivalent expressions are intended to include compounds of Formula I as well as pharmaceutically acceptable salts.

As used herein, the term "isotopic variation" refers to a compound that contains ratios of isotopes greater than their natural abundance at one or more atoms that constitute the compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more radioactive isotopes, or may be labeled with a non-radioactive isotope, such as deuterium ( ^2H or D), carbon-13 ( ^13C ), nitrogen 15 ( ¹⁵ N) and so on. It is understood that in compounds undergoing such isotopic substitution, the following atoms, if present, may vary, so for example, any hydrogen may be ² H/D, any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N, and The presence and location of such atoms can be determined within the skill in the art.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers", such as diastereomers, enantiomers and atropisomers. Compounds of the present disclosure may possess one or more asymmetric centers; thus, such compounds may be produced at each asymmetric center as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, any description or designation of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof, racemic or otherwise. When a chiral center is present in a structure, but the specific stereochemistry of that center is not shown, then both enantiomers (alone or as a mixture of enantiomers) are encompassed by the structure. When more than one chiral center is present in a structure, but the specific stereochemistry of said center is not shown, all enantiomers and diastereomers (alone or as a mixture) are encompassed by that structure. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

See, eg, US Patent Application Serial No. 16/679,105.

In some aspects, the disclosure relates to a crystalline form of a compound of formula I,

In some embodiments, the present disclosure relates to crystalline Form I (Formula I-Form I) of the compound of Formula I. In some embodiments, Formula I - Form I is substantially free of any other solid forms of Formula I.

In some embodiments, Formula I - Form I exhibits an XRPD substantially as shown in FIG. 1 . The XRPD of Formula I-Form I shown in Figure 1 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 1:

Table 1. XRPD data for the crystalline forms of Formula I-Form I shown in Figure 1.

In some embodiments of the present disclosure, Formula I - Form I is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 1. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 1 above. In other aspects, Formula I - Form I is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 1 above.

In some embodiments, Formula I - Form I is characterized by an XRPD pattern comprising peaks at 11.2, 13.9, 17.1, 17.7, and 20.8 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form I is characterized by an XRPD pattern comprising peaks at 9.4, 11.2, 13.9, 17.1, and 17.7 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form I is characterized by an XRPD pattern comprising peaks at 17.1, 17.7, 20.8, and 21.9 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form I is characterized by an XRPD pattern comprising peaks at 13.9, 17.1, 17.7, 20.8, and 21.9 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form I is characterized by an XRPD pattern comprising peaks at 11.2, 13.9, 17.1, 17.7, 20.8, 21.9, and 25.0 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form I is characterized by an XRPD pattern comprising peaks at 9.4, 11.2, 13.9, 17.1, 17.7, 20.8, 21.9, 25.0, and 27.8 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, Formula I-Form I is characterized by comprising XRPD pattern of the peak.

In some embodiments, Formula I-Form I can be characterized by a DSC thermogram substantially as shown in FIG. 2 . As shown in Figure 2, when heated at a rate of 10°C/min, Formula I-Form I produced an endothermic peak at 81.29°C with a peak onset temperature of 66.26°C and an enthalpy of fusion of 36.11 J/g. In some embodiments of the present disclosure, Formula I - Form I is characterized by a DSC thermogram comprising an endothermic peak at about 81°C. In other embodiments of the present disclosure, Formula I - Form I is characterized by a DSC enthalpy of fusion of about 36 J/g.

In some embodiments, Formula I - Form I can be characterized by a TGA curve substantially as shown in Figure 3 when heated at a rate of 20°C/min. As shown in Figure 3, Formula I - Form I lost about 76% of its weight when heated to about 430°C.

In some embodiments of the present disclosure, Formula I - Form I is characterized by comprising a peak at one or more of 9.4, 11.2, 13.9, 17.1, 17.7, 20.8, 21.9, 25.0, and 27.8 degrees ± 0.2 degrees 2Θ and a DSC thermogram including an endothermic peak at about 81°C when heated at a rate of 10°C/min.

In some embodiments, the present invention relates to crystalline Form II (Formula I-Form II) of the compound of Formula I. In some embodiments, Formula I-Form II is substantially free of any other solid forms of Formula I.

In some embodiments, Formula I-Form II exhibits an XRPD substantially as shown in FIG. 6 . The XRPD of formula I-form II shown in Figure 6 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 2:

Table 2. XRPD data for the crystalline forms of Formula I-Form II shown in Figure 6.

In some embodiments of the present disclosure, Formula I-Form II is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 2. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 2 above. In other aspects, Formula I - Form II is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 2 above.

In some embodiments, Formula I-Form II is characterized by an XRPD pattern comprising peaks at 9.2, 21.7, and 30.5 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I-Form II is characterized by an XRPD pattern comprising peaks at 9.2, 12.6, 17.4, and 30.5 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form II is characterized by an XRPD pattern comprising peaks at 17.4, 18.1, 19.3, 19.8, and 21.7 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form II is characterized by an XRPD pattern comprising peaks at 17.4, 18.1, 19.3, 19.8, and 30.5 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form II is characterized by an XRPD pattern comprising peaks at 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, and 30.5 degrees ± 0.2 degrees 2Θ. In other embodiments, Formula I - Form II is characterized by an XRPD pattern comprising peaks at 9.2, 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, 30.5, and 34.9 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, Formula I-Form II is characterized by two or more of 9.2, 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, 30.5, and 34.9 degrees ± 0.2 degrees 2Θ The XRPD pattern of the peaks is included here.

In some embodiments, Formula I-Form II can be characterized by a DSC thermogram substantially as shown in FIG. 7 . As shown in Figure 7, when heated at a rate of 10°C/min, Formula I-Form II produces an endothermic peak at 68.06°C, where the peak onset temperature is 64.20°C, and the melting enthalpy is 22.71 J/g, followed by An endothermic peak at 91.90°C was generated with a peak onset temperature of 85.85°C and an enthalpy of fusion of 114.7 J/g. In some embodiments of the present disclosure, Formula I-Form II is characterized by a DSC thermogram comprising an endothermic peak at about 68°C. In other embodiments of the present disclosure, Formula I-Form II is characterized by a DSC enthalpy of fusion of about 23 J/g. In other embodiments, Formula I-Form II is characterized by a DSC thermogram comprising an endothermic peak at about 92°C. In other embodiments of the present disclosure, Formula I-Form II is characterized by a DSC enthalpy of fusion of about 115 J/g.

In some embodiments of the present disclosure, Formula I-Form II is characterized by at one or more of 9.2, 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, 30.5, and 34.9 degrees ± 0.2 degrees 2Θ XRPD pattern including peaks, and DSC thermogram including an endothermic peak at about 68°C when heated at a rate of 10°C/min.

In some embodiments, the present disclosure is directed to a choline salt of a compound of Formula I, which has Formula IA:

In some embodiments, the present disclosure relates to a crystalline form of the choline salt of the compound of Formula I.

In some embodiments, the choline salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the choline salt of Formula I exhibits an XRPD substantially as shown in FIG. 8 . The XRPD of the choline salt of formula I shown in Figure 8 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 3:

Table 3. XRPD data for the crystalline form of the choline salt of Formula I (Formula IA) shown in Figure 8.

In some embodiments of the present disclosure, the choline salt of Formula I is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 3. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 3 above. In other aspects, the choline salt of Formula I is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 3 above.

In some embodiments, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at 19.4 and 20.0 degrees ± 0.2 degrees 2Θ. In other embodiments, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at 18.5, 19.4, 20.0, and 22.6 degrees ± 0.2 degrees 2Θ. In other embodiments, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at 13.3, 18.5, 19.4, 20.0, and 22.6 degrees ± 0.2 degrees 2Θ. In other embodiments, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at 9.9, 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the choline salt of Formula I is characterized by an XRPD comprising peaks at two or more of 9.9, 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2Θ Atlas.

In some embodiments, the choline salt of Formula I can be characterized by a DSC thermogram substantially as shown in FIG. 9 . As shown in Figure 9, when heated at a rate of 10°C/min, the choline salt of Formula I produced an endothermic peak at 157.97°C with a peak onset temperature of 148.62°C and an enthalpy of fusion of 22.76 J/g. In some embodiments of the present disclosure, the choline salt of Formula I is characterized by a DSC thermogram comprising an endothermic peak at about 158°C. In other embodiments of the present disclosure, the choline salt of Formula I is characterized by a DSC enthalpy of fusion of about 23 J/g.

In some embodiments of the present disclosure, the choline salt of Formula I is characterized by an XRPD pattern comprising peaks at one or more of 9.9, 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2Θ , and a DSC thermogram comprising an endothermic peak at about 158°C when heated at a rate of 10°C/min.

In some embodiments of the present disclosure, the choline salt of Formula I is characterized by a TGA curve substantially as shown in FIG. 10 . As shown in Figure 10, the choline salt of Formula I lost about 4.7% by weight when heated at 20°C/min to 250°C.

In some embodiments, the present disclosure relates to a benzathine salt of a compound of formula I, which has the formula IB:

In some embodiments, the present disclosure relates to a crystalline form of the benzathine salt of the compound of Formula I.

In some embodiments, the benzathine salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the benzathine salt of Formula I exhibits an XRPD substantially as shown in FIG. 12 . The XRPD of the benzathine salt of formula I shown in Figure 12 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 4:

Table 4. XRPD data for the crystalline form of the benzathine salt of Formula I (Formula IB) shown in Figure 12.

In some embodiments of the present disclosure, the benzathine salt of Formula I is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 4. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 4 above. In other aspects, the benzathine salt of Formula I is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 4 above.

In some embodiments, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at 5.8 and 18.2 degrees ± 0.2 degrees 2Θ. In other embodiments, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at 5.8, 16.6, and 18.2 degrees ± 0.2 degrees 2Θ. In other embodiments, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at 5.8, 16.6, 18.2, and 20.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at 5.8, 12.6, 16.6, 18.2, and 22.2 degrees ± 0.2 degrees 2Θ. In other embodiments, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at 5.8, 12.6, 16.6, 18.2, and 20.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at 5.8, 12.6, 16.6, 18.2, 20.7, and 22.2 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at two or more of 5.8, 12.6, 16.6, 18.2, 20.7, and 22.2 degrees ± 0.2 degrees 2Θ.

In some embodiments, the benzathine salt of Formula I can be characterized by a DSC thermogram substantially as shown in FIG. 13 . As shown in Figure 13, when heated at a rate of 10°C/min, the benzathine salt of Formula I produces an endothermic peak at 111.71°C with a peak onset temperature of 108.04°C and an enthalpy of fusion of 42.55 J/g. In some embodiments of the present disclosure, the benzathine salt of Formula I is characterized by a DSC thermogram comprising an endothermic peak at about 112°C. In other embodiments of the present disclosure, the benzathine salt of Formula I is characterized by a DSC enthalpy of fusion of about 43 J/g.

In some embodiments of the present disclosure, the benzathine salt of Formula I is characterized by an XRPD pattern comprising peaks at one or more of 5.8, 12.6, 16.6, 18.2, 20.7, and 22.2 degrees ± 0.2 degrees 2Θ, and DSC thermogram including an endothermic peak at about 112°C when heated at a rate of 10°C/min.

In some embodiments of the present disclosure, the benzathine salt of Formula I is characterized by a TGA curve substantially as shown in FIG. 14 . As shown in Figure 14, the benzathine salt of Formula I lost about 35.2% by weight when heated at 20°C/min to 300°C.

In some embodiments, the present disclosure relates to imidazolium salts of compounds of formula I, which have the formula IC:

In some embodiments, the present disclosure relates to a crystalline form of the imidazolium salt of the compound of formula I.

In some embodiments, the imidazolium salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the imidazolium salt of Formula I exhibits an XRPD substantially as shown in FIG. 16 . The XRPD of the imidazolium salt of formula I shown in Figure 16 comprises reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in table 5:

Table 5. XRPD data for the crystalline form of the imidazolium salt of Formula I (Formula IC) shown in Figure 16.

In some embodiments of the present disclosure, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 5. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 5 above. In other aspects, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 5 above.

In some embodiments, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising peaks at 14.1 and 17.0 degrees ± 0.2 degrees 2Θ. In other embodiments, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising peaks at 14.1, 17.0, 17.9, 18.8, and 20.6 degrees ± 0.2 degrees 2Θ. In other embodiments, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising peaks at 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, and 23.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising peaks at 6.5, 7.0, 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, and 23.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising peaks at 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, 23.8, 24.4, and 26.5 degrees ± 0.2 degrees 2Θ. In other embodiments, the imidazolium salt of Formula I is characterized by an XRPD pattern comprising peaks at 6.5, 7.0, 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, 23.8, 24.4, and 26.5 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the imidazolium salt of Formula I is characterized by being at two of 6.5, 7.0, 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, 23.8, 24.4, and 26.5 degrees ± 0.2 degrees 2Θ or more XRPD patterns including peaks.

In some embodiments, the imidazolium salt of Formula I can be characterized by a DSC thermogram substantially as shown in FIG. 17 . As shown in Figure 17, when heated at a rate of 10°C/min, the imidazolium salt of Formula I produced an endothermic peak at 134.56°C with a peak onset temperature of 130.50°C and a melting enthalpy of 9.069 J/g. In some embodiments of the present disclosure, the imidazolium salt of Formula I is characterized by a DSC thermogram comprising an endothermic peak at about 135°C. In other embodiments of the present disclosure, the imidazolium salt of Formula I is characterized by a DSC enthalpy of fusion of about 9.1 J/g.

In some embodiments of the present disclosure, the imidazolium salt of Formula I is characterized by one of 6.5, 7.0, 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, 23.8, 24.4, and 26.5 degrees ± 0.2 degrees 2Θ An XRPD pattern that includes peaks at one or more places, and a DSC thermogram that includes an endothermic peak at about 135°C when heated at a rate of 10°C/min.

In some embodiments of the present disclosure, the imidazolium salt of Formula I is characterized by a TGA curve substantially as shown in FIG. 18 . As shown in Figure 18, the imidazolium salt of formula I lost about 4.7% by weight when heated to 200°C at 20°C/min.

In some embodiments, the present disclosure relates to piperazine salts of compounds of formula I, having the formula ID:

In some embodiments, the present disclosure relates to a crystalline form of the piperazine salt of Formula I.

In some embodiments, the piperazine salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the piperazine salt of Formula I (Form 1) exhibits an XRPD substantially as shown in FIG. 20 . The XRPD of the piperazine salt of formula I shown in Figure 20 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 6:

Table 6. XRPD data for the crystalline form of the piperazine salt of Formula I shown in Figure 20 (Formula ID - Form 1).

In some embodiments of the present disclosure, the piperazine salt of Formula 1 (Form 1) (Form 1) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 6. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 6 above. In other aspects, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 6 above.

In some embodiments, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising peaks at 7.1, 12.2, and 14.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising peaks at 7.1, 12.2, 14.8, and 16.0 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, and 17.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, 17.9, and 19.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, and 20.5 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula 1 (Form 1) is characterized by an XRPD pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, 20.5, and 22.8 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the piperazine salt of Formula 1 (Form 1) is characterized by two or more of 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, 20.5, and 22.8 degrees ± 0.2 degrees 2Θ where the XRPD pattern of the peak is included.

In some embodiments, the piperazine salt of Formula 1 (Form 1) can be characterized by a DSC thermogram substantially as shown in FIG. 21 . As shown in Figure 21, when heated at a rate of 10°C/min, the piperazine salt of Formula 1 (Form 1) produces an endothermic peak at 160.50°C with a peak onset temperature of 150.65°C and an enthalpy of fusion of 39.04 J/g. In some embodiments of the present disclosure, the piperazine salt of Formula 1 (Form 1) is characterized by a DSC thermogram comprising an endothermic peak at about 160°C. In other embodiments of the present disclosure, the piperazine salt of Formula 1 (Form 1) is characterized by a DSC enthalpy of fusion of about 39 J/g.

In some embodiments of the present disclosure, the piperazine salt of Formula 1 (Form 1) is characterized by one or more of 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, 20.5, and 22.8 degrees ± 0.2 degrees 2Θ The XRPD pattern includes a peak at , and the DSC thermogram includes an endothermic peak at about 160°C when heated at a rate of 10°C/min.

In some embodiments of the present disclosure, the piperazine salt of Formula 1 (Form 1) is characterized by a TGA curve substantially as shown in FIG. 22 . As shown in Figure 22, the piperazine salt of Formula 1 (Form 1) lost about 14.3% by weight when heated at 20°C/min to 300°C.

In some embodiments, the piperazine salt of Formula I (Form 2) exhibits an XRPD substantially as shown in Figure 20A. The XRPD of the piperazine salt of Formula I (Form 2) shown in Figure 20A includes reflection angle (degrees 2θ ± 0.2 degrees 2θ), line distance (d value) and relative intensity, as shown in Table 6A:

Table 6A. XRPD data for the crystalline form of the piperazine salt of Formula I (Formula ID - Form 2) shown in Figure 20A.

In some embodiments of the present disclosure, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 6A. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 6A above. In other aspects, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 6A above.

In some embodiments, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 16.5 and 17.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 5.5, 6.2, 8.6, 14.0, 16.5, and 17.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 5.5, 6.2, 8.6, 14.0, 16.5, 17.8, 19.1, and 20.5 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 8.6, 14.0, 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 5.5, 6.2, 8.6, 14.0, 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2Θ .

In some embodiments of the present disclosure, the piperazine salt of Formula I (Form 2) is characterized by two degrees of XRPD patterns that include peaks at one or more places.

In some embodiments, the piperazine salt of Formula I (Form 2) can be characterized by a DSC thermogram substantially as shown in Figure 21A. As shown in Figure 21A, when heated at a rate of 10°C/min, the piperazine salt of Formula I (Form 2) produces an endothermic peak at 142.60°C with a peak onset temperature of 139.29°C and an enthalpy of fusion of 6.904 J/g. In some embodiments of the present disclosure, the piperazine salt of Formula I (Form 2) is characterized by a DSC thermogram comprising an endothermic peak at about 143°C. In other embodiments of the present disclosure, the piperazine salt of Formula I (Form 2) is characterized by a DSC enthalpy of fusion of about 6.9 J/g.

In some embodiments of the present disclosure, the piperazine salt of Formula I (Form 2) is characterized by one of 5.5, 6.2, 8.6, 14.0, 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2Θ An XRPD pattern that includes peaks at one or more locations, and a DSC thermogram that includes an endothermic peak at about 143°C when heated at a rate of 10°C/min.

In some embodiments, the piperazine salt of Formula I (Form 3) exhibits an XRPD substantially as shown in Figure 20B. The XRPD of the piperazine salt of Formula I (Form 3) shown in Figure 20B includes reflection angle (degrees 2θ ± 0.2 degrees 2θ), line distance (d value) and relative intensity, as shown in Table 6B:

Table 6B. XRPD data for the crystalline form of the piperazine salt of Formula I (Formula ID - Form 3) shown in Figure 20B.

In some embodiments of the present disclosure, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 6B. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 6B above. In other aspects, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 6B above.

In some embodiments, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising peaks at 18.5, 19.4, and 19.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising peaks at 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising peaks at 13.8, 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising peaks at 11.6, 13.8, 16.5, 16.9, 18.5, 19.4, and 19.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 3) is characterized by an XRPD pattern comprising peaks at 11.6, 13.8, 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperazine salt of Formula I (Form 3) is characterized by including peaks at 6.3, 6.7, 11.0, 11.6, 13.8, 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2Θ. XRPD pattern.

In some embodiments of the present disclosure, the piperazine salt of Formula I (Form 3) is characterized by a temperature of XRPD patterns that include peaks at two or more of .

In some embodiments, the present disclosure relates to piperidinium salts of compounds of Formula I, having Formula IE:

In some embodiments, the present disclosure relates to a crystalline form of the piperidine salt of Formula I.

In some embodiments, the piperidine salt of Formula I is substantially free of any other salt or solid form of Formula I.

In some embodiments, the piperidine salt of Formula I (Form 1) exhibits an XRPD substantially as shown in FIG. 24 . The XRPD of the piperidine salt of Formula I (Form 1) shown in Figure 24 includes reflection angle (degrees 2θ ± 0.2 degrees 2θ), line distance (d value) and relative intensity, as shown in Table 7:

Table 7. XRPD data for the crystalline form of the piperidine salt of Formula I shown in Figure 24 (Formula IE-Form 1).

In some embodiments of the present disclosure, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 7. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 7 above. In other aspects, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 7 above.

In some embodiments, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 7.3 and 17.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 7.3, 12.2, 16.1, and 17.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 7.3, 12.2, 14.3, 14.8, 16.1, and 17.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, and 19.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, 19.8, and 20.6 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, 19.8, 20.6, and 22.9 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the piperidinium salt of Formula I (Form 1) is characterized by either of 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, 19.8, 20.6, and 22.9 degrees ± 0.2 degrees 2Θ or XRPD patterns of peaks are included at more.

In some embodiments, the piperidine salt of Formula I (Form 1) can be characterized by a DSC thermogram substantially as shown in FIG. 25 . As shown in Figure 25, when heated at a rate of 10°C/min, the piperidine salt of Formula 1 (Form 1) produces an endothermic peak at 174.17°C with a peak onset temperature of 161.09°C and an enthalpy of fusion of 59.20 J/g. In some embodiments of the present disclosure, the piperidine salt of Formula I (Form 1) is characterized by a DSC thermogram comprising an endothermic peak at about 174°C. In other embodiments of the present disclosure, the piperidinium salt of Formula I (Form 1) is characterized by a DSC enthalpy of fusion of about 59 J/g.

In some embodiments of the present disclosure, the piperidine salt of Formula I (Form 1) is characterized by one of 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, 19.8, 20.6, and 22.9 degrees ± 0.2 degrees 2Θ or The XRPD pattern includes peaks at several places, and the DSC thermogram includes an endothermic peak at about 174°C when heated at a rate of 10°C/min.

In some embodiments of the present disclosure, the piperidinium salt of Formula I (Form 1) is characterized by a TGA curve substantially as shown in FIG. 26 . As shown in Figure 26, the piperidine salt of Formula I (Form 1) lost about 17.6 wt% when heated to 300°C at 20°C/min.

In some embodiments, the piperidine salt of Formula I (Form 2) exhibits an XRPD substantially as shown in Figure 24A. The XRPD of the piperidine salt of Formula I (Form 2) shown in Figure 24A includes reflection angle (degrees 2θ ± 0.2 degrees 2θ), line distance (d value) and relative intensity, as shown in Table 7A:

Table 7A. XRPD data for the crystalline form of the piperidine salt of Formula I (Formula IE-Form 2) shown in Figure 24A.

In some embodiments of the present disclosure, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 7A. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 7A above. In other aspects, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 7A above.

In some embodiments, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising a peak at 18.3 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 16.8 and 18.3 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 10.9, 16.8, and 18.3 degrees ± 0.2 degrees 2Θ. In other embodiments, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 16.8, 18.3, and 20.7 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the piperidine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at two or more of 10.9, 16.8, 18.3, and 20.7 degrees ± 0.2 degrees 2Θ.

In some embodiments, the present disclosure is directed to a potassium salt of a compound of formula I having the formula IF:

In some embodiments, the potassium salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the potassium salt of Formula I exhibits an XRPD substantially as shown in FIG. 28 . The XRPD of the potassium salt of formula I shown in Figure 28 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 8:

Table 8. XRPD data for the crystalline form of the potassium salt of Formula I (Formula IF) shown in Figure 28.

In some embodiments of the present disclosure, the potassium salt of Formula I is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 8. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 8 above. In other aspects, the potassium salt of Formula I is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 8 above.

In some embodiments, the potassium salt of Formula I is characterized by an XRPD pattern comprising peaks at 9.1, 10.4, 18.0, and 19.3 degrees ± 0.2 degrees 2Θ. In other embodiments, the potassium salt of Formula I is characterized by an XRPD pattern comprising peaks at 10.4, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2Θ. In other embodiments, the potassium salt of Formula I is characterized by an XRPD pattern comprising peaks at 9.1, 10.4, 19.3, and 22.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the potassium salt of Formula I is characterized by an XRPD pattern comprising peaks at 9.1, 10.4, 18.0, 19.3, and 24.4 degrees ± 0.2 degrees 2Θ. In other embodiments, the potassium salt of Formula I is characterized by an XRPD pattern comprising peaks at 9.1, 10.4, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2Θ. In other embodiments, the potassium salt of Formula I is characterized by an XRPD pattern comprising peaks at 9.1, 10.4, 15.1, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the potassium salt of Formula I is characterized by including peaks at two or more of 9.1, 10.4, 12.5, 15.1, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2Θ. XRPD pattern.

In some embodiments, the potassium salt of Formula I can be characterized by a DSC thermogram substantially as shown in FIG. 29 . As shown in Figure 29, when heated at a rate of 10°C/min, the potassium salt of formula I produced an endothermic peak at 149.53°C with a peak onset temperature of 135.10°C and an enthalpy of fusion of 45.20 J/g. In some embodiments of the present disclosure, the potassium salt of Formula I is characterized by a DSC thermogram comprising an endothermic peak at about 150°C. In other embodiments of the present disclosure, the potassium salt of Formula I is characterized by a DSC enthalpy of fusion of about 45 J/g.

In some embodiments of the present disclosure, the potassium salt of Formula I is characterized by an XRPD comprising peaks at one or more of 9.1, 10.4, 12.5, 15.1, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2Θ spectrum, and a DSC thermogram including an endothermic peak at about 150°C when heated at a rate of 10°C/min.

In some embodiments, the present disclosure relates to (S)-(-)-α-methylbenzylamine salts of compounds of formula I, having the formula IG:

In some embodiments, the present disclosure relates to a crystalline form of Formula I (S)-(-)-α-methylbenzylamine salt.

In some embodiments, the (S)-(-)-α-methylbenzylamine salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the (S)-(-)-α-methylbenzylamine salt of Formula I exhibits an XRPD substantially as shown in FIG. 30 . The XRPD of (S)-(-)-α-methylbenzylamine salt of formula I shown in Figure 30 includes reflection angle (degree 2θ ± 0.2 degree 2θ), line distance (d value) and relative intensity, as shown in Table 9 Shown:

Table 9. XRPD data for the crystalline form of (S)-(-)-α-methylbenzylamine salt of Formula I (Formula IG) shown in Figure 30.

In some embodiments of the present disclosure, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 9. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 9 above. In other aspects, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 9 above.

In some embodiments, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising a peak at 18.2 degrees ± 0.2 degrees 2Θ. In other embodiments, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising a peak at 19.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by an XRPD pattern comprising peaks at 18.2 and 19.9 degrees ± 0.2 degrees 2Θ.

In some embodiments, (S)-(-)-α-methylbenzylamine salt of Formula I can be characterized by a DSC thermogram substantially as shown in FIG. 31 . As shown in Figure 31, when heated at a rate of 10 °C/min, the (S)-(-)-α-methylbenzylamine salt of formula I produces an endothermic peak at 75.30 °C, where the peak onset temperature is 47.77°C with a melting enthalpy of 106.3 J/g followed by an endothermic peak at 113.73°C with a peak onset temperature of 108.86°C and a melting enthalpy of 16.39 J/g. In some embodiments of the present disclosure, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by a DSC thermogram comprising an endothermic peak at about 75°C. In other embodiments of the present disclosure, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by a DSC enthalpy of fusion of about 106.3 J/g. In some embodiments of the present disclosure, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by a DSC thermogram comprising an endothermic peak at about 114°C. In other embodiments of the present disclosure, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by a DSC enthalpy of fusion of about 16.4 J/g.

In some embodiments of the present disclosure, the (S)-(-)-α-methylbenzylamine salt of Formula I is characterized by including peaks at one or more of 18.2 and 19.9 degrees ± 0.2 degrees 2Θ XRPD pattern, and DSC thermogram including an endothermic peak at about 75°C or about 114°C when heated at a rate of 10°C/min.

In some embodiments, the present disclosure relates to ethylenediamine salts of compounds of formula I, having the formula IH:

In some embodiments, the present disclosure relates to a crystalline form of the ethylenediamine salt of the compound of formula I.

In some embodiments, the ethylenediamine salt of Formula I is substantially free of any other salts or solid forms of Formula I.

In some embodiments, the ethylenediamine salt of Formula I (Form 1) exhibits an XRPD substantially as shown in FIG. 32 . The XRPD of the ethylenediamine salt of Formula I (Form 1) shown in Figure 32 includes reflection angle (degrees 2Θ ± 0.2 degrees 2Θ), line distance (d value) and relative intensity, as shown in Table 10:

Table 10. XRPD data for the crystalline form of the ethylenediamine salt of Formula I shown in Figure 32 (Formula IH-Form 1).

In some embodiments of the present disclosure, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 10. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 10 above. In other aspects, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 10 above.

In some embodiments, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 9.4, 10.6, 17.7, and 18.3 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, and 18.3 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, 18.3, and 19.6 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, and 22.0 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, 22.0, and 23.1 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 1) is characterized by an XRPD pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, 22.0, 23.1, and 24.8 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the ethylenediamine salt of Formula I (Form 1) is characterized by being at two of 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, 22.0, 23.1, and 24.8 degrees ± 0.2 degrees 2Θ or more XRPD patterns including peaks.

In other embodiments, the ethylenediamine salt of Formula I (Form 2) exhibits an XRPD substantially as shown in Figure 32A. The XRPD of the ethylenediamine salt of Formula I (Form 2) shown in Figure 32A includes reflection angle (degrees 2θ ± 0.2 degrees 2θ), line distance (d value) and relative intensity, as shown in Table 11:

Table 11. XRPD data for the crystalline form of the ethylenediamine salt of Formula I (Formula IH-Form 2) shown in Figure 32A.

In some embodiments of the present disclosure, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 11. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising more than one peak at one of the angles listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising two peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising three peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising four peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising five peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising six peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising seven peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising eight peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising nine peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising ten peaks at angles selected from those listed in Table 11 above. In other aspects, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising more than ten peaks at angles selected from those listed in Table 11 above.

In some embodiments, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising a peak at 17.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 17.8 and 21.8 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 17.8, 21.8, and 22.7 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 17.8, 21.8, 22.7, and 25.9 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 17.8, 21.8, 22.7, 25.9, and 29.5 degrees ± 0.2 degrees 2Θ. In other embodiments, the ethylenediamine salt of Formula I (Form 2) is characterized by an XRPD pattern comprising peaks at 17.8, 21.8, 22.7, 25.9, 29.5, and 35.7 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the ethylenediamine salt of Formula I (Form 2) is characterized by comprising XRPD pattern of the peak.

In some embodiments, the present disclosure is directed to a 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of a compound of Formula I, which has the Formula IK:

In some embodiments, the present disclosure relates to a crystalline form of Formula I 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt.

In some embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is substantially free of any other salt or solid form of Formula I.

In some embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I exhibits an XRPD substantially as shown in FIG. 34 . The XRPD of the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I shown in Figure 34 includes reflection angle (degrees 2θ ± 0.2 degrees 2θ), line spacing (d value ) and relative strength, as shown in Table 12:

Table 12. XRPD data for the crystalline form of 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I (Formula IK) shown in Figure 34.

In some embodiments of the present disclosure, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by one of the angles listed in Table 12 The XRPD pattern of the peaks is included here. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising more than XRPD pattern of one peak. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising two peaks at angles selected from those listed in Table 12 above XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising three peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising four peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising five peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising six peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising seven peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising eight peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising nine peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising ten peaks at angles selected from those listed in Table 12 above. XRPD pattern. In other aspects, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by comprising more than ten angles selected from those listed in Table 12 above. XRPD pattern of the peak.

In some embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by including peaks at 16.3, 17.2, and 18.0 degrees ± 0.2 degrees 2Θ. XRPD pattern. In other embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by ±0.2 XRPD pattern including peaks at degrees 2Θ. In other embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized in that XRPD pattern including peaks at ±0.2 degrees 2Θ. In other embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by 7.3, 12.2, 12.8, 16.3, and 17.2 degrees ± 0.2 degrees 2Θ The XRPD pattern of the peaks is included here. In other embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I is characterized in that at 7.3,12.2,12.8,16.3,17.2,18.0,20.8 and The XRPD pattern included a peak at 23.2 degrees ± 0.2 degrees 2Θ. In other embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I is characterized in that at 7.3,12.2,12.8,16.3,17.2,18.0,20.8, The XRPD pattern included peaks at 23.2, 24.3, and 26.6 degrees ± 0.2 degrees 2Θ.

In some embodiments of the present disclosure, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I is characterized by XRPD patterns that include peaks at two or more of , 20.8, 23.2, 24.3, and 26.6 degrees ± 0.2 degrees 2Θ.

In some embodiments, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I can be characterized by a DSC thermogram substantially as shown in FIG. 35 . As shown in Figure 35, when heated at a rate of 10°C/min, 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I produces an endotherm at 170.34°C peak with a peak onset temperature of 161.07°C and an enthalpy of fusion of 41.18 J/g. In some embodiments of the present disclosure, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by a DSC heat value including an endothermic peak at about 170°C. spectrogram. In other embodiments of the present disclosure, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by a DSC enthalpy of fusion of about 41 J/g.

In some embodiments of the present disclosure, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I is characterized by , 20.8, 23.2, 24.3, and 26.6 degrees ± 0.2 degrees 2θ at one or more of the XRPD pattern including peaks, and the DSC heat including an endothermic peak at about 170°C when heated at a rate of 10°C/min spectrogram.

In some embodiments of the present disclosure, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I is characterized by a TGA curve substantially as shown in FIG. 36 . As shown in Figure 36, the 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of Formula I lost about 13.5% by weight when heated at 20°C/min to 250°C.

Pharmaceutical compositions and methods of administration

The subject pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure as an active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. If necessary, the pharmaceutical composition contains a pharmaceutically acceptable salt and/or its coordination complex, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers) ), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants.

A subject pharmaceutical composition may be administered alone or in combination with one or more other agents, which are also typically administered in the form of a pharmaceutical composition. If necessary, one or more compounds of the present invention and other agents may be mixed into a formulation, or both components may be formulated into separate formulations to use them alone or in combination at the same time.

In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition of the invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% , 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3 %, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006% .

In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% , 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75% %, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50% , 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2% , 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06 %, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within the range defined by any two figures above and including them), the above percentages are based on w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of the invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, About 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09 % to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% about In the range of 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10%, the above percentages are based on w/w, w/v or v /v.

In some embodiments, one or more compounds of the invention are present at a concentration of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, About 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1 % to about 0.9%, the above percentages being based on w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g , 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004 g, 0.0003g, 0.0002g or 0.0001g (or a number within a range defined by any two of the above numbers and including them).

In some embodiments, the amount of one or more compounds of the invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g , 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.009g, 0.015 g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.09g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g , 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or defined by and including any two of the above numbers).

In some embodiments, the amount of one or more compounds of the invention is 0.0001-10g, 0.0005-9g, 0.001-8g, 0.005-7g, 0.01-6g, 0.05-5g, 0.1-4g, 0.5-4g or In the range of 1-3g.

The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg/day, and 5 to 40 mg/day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg/day. The exact dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

The pharmaceutical composition of the present invention usually contains the active ingredient of the present invention (i.e., the disclosed compound) or its pharmaceutically acceptable salt and/or coordination complex, and one or more pharmaceutically acceptable excipients Excipients, carriers (including but not limited to inert solid diluents and fillers), diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositions and methods for their preparation.

Pharmaceutical compositions for oral administration .

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and ( iii) Pharmaceutical excipients suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the present invention suitable for oral administration may be presented in discrete dosage forms such as capsules, cachets or tablets, or liquid or aerosol sprays (each containing a predetermined amount of the active ingredient in powder or granule form), solutions. , or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions. Such dosage forms may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired appearance. For example, a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally with excipients such as, but not limited to, binders, lubricants, inert diluents and/or surface active ingredients. agent or dispersant mixture. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water may facilitate the degradation of some compounds. For example, in the pharmaceutical field water (eg, 5%) can be added as a means of simulating long term storage to determine properties such as shelf life or stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention that contain lactose can be rendered anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging and/or storage is expected. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is preserved. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics and the like, unit dose containers, blister packs, and strip packs.

The active ingredient can be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used as carrier, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations, such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants As a carrier for the detoxification agent, lactose is not used in some embodiments. For example, suitable carriers include powders, capsules and tablets, as well as solid oral formulations. Tablets may be coated, if desired, by standard aqueous or non-aqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth Gum, guar gum, cellulose and its derivatives (e.g. ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized Starch, hydroxypropyl methylcellulose, microcrystalline cellulose and mixtures thereof.

Examples of suitable fillers for the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, Kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof.

Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that may disintegrate in the bottle. Too little may not be sufficient for disintegration to occur and thus may alter the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant, neither too little nor too much, to deleteriously alter the release of the active ingredient can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary depending on the type of formulation and mode of administration and will be readily discernible to one of ordinary skill in the art. From about 0.5 to about 15 weight percent disintegrant, or from about 1 to about 5 weight percent disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, pollac Lin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starches, other starches, clay, other algae, other celluloses, gums or mixtures thereof.

Lubricants that may be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol Alcohols, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, oil Ethyl laurate, ethyl laurate, agar or mixtures thereof. Additional lubricants include, for example, syloid silica gels, condensation aerosols of synthetic silica, or mixtures thereof. A lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are required for oral administration, the active ingredient may be mixed with various sweetening or flavoring agents, coloring or dyeing agents and, if desired, emulsifying and/or suspending agents, and, for example, Water, ethanol, propylene glycol, glycerin, and diluents of various combinations thereof are combined together.

Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a longer sustained action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, Mixed with liquid paraffin or olive oil.

Surfactants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphiles is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.

Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which an HLB rating is generally not applicable. Similarly, lipophilic (ie, hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline commonly used in the formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin ; lyso-lecithin and hydrogenated lyso-lecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; docusate sodium; Mono- and di-acetylated tartrates of glycerides and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

In the above group, ionic surfactants include, for example: lecithin, lyso-lecithin, phospholipids, lyso-phospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; docusate sodium; Lactate; mono- and diacetylated tartrates of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof .

The ionic surfactant can be lecithin, lyso-lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lyso Phosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate of fatty acids, stearoyl-2-lactate, stearoyl lactylate, succinyl monoglyceride, mono Mono/Di-Acetylated Tartrate of Diglycerides, Citrate of Mono/Diglycerides, Cholyl Sarcosine, Caproate, Caprylate, Caprate, Laurate, Myristate, Palmitate, Oleate, Ricinoleate, Linoleate, Linolenate, Stearate, Lauroyl Sulfate, Tetraacetyl Sulfate, Docusate, Lauroyl Carnitine, Palmitoyl Carnitine , the ionized form of myristoylcarnitine and its salts and mixtures.

Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkylthioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol Alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol Alcohol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; polyols with glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols Hydrophilic transesterification products of at least one member of: polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and A mixture; a hydrophilic transesterification product of polyethylene glycol sorbitan fatty acid esters and polyols with at least one member of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or sugars.

Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 Laurate, PEG-12 Laurate, PEG-20 Laurate, PEG-32 Laurate, PEG-32 Dilaurate, PEG -12 Oleate, PEG-15 Oleate, PEG-20 Oleate, PEG-20 Dioleate, PEG-32 Oleate, PEG-200 Oleate, PEG-400 Oleate, PEG -15 Stearate, PEG-32 Distearate, PEG-40 Stearate, PEG-100 Stearate, PEG-20 Dilaurate, PEG-25 Triolein, PEG -32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG- 30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric/Caprylic Glycerides, PEG-8 Capric/Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG -25 Phytosterol, PEG-30 Soy Sterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate Ester 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG- 24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octyl Phenol series and poloxamer (poloxamer).

By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; Glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; mono- and diglycerides of lactic acid Derivatives; hydrophobic transesterification products of polyols with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include fatty acid esters of glycerol, fatty acid esters of propylene glycol, and mixtures thereof, or hydrophobic transesterification of polyols with at least one member of vegetable oils, hydrogenated vegetable oils, and triglycerides product.

In one embodiment, the composition may comprise solubilizers to ensure good solubilization and/or dissolution of the compounds of the invention and to minimize precipitation of the compounds of the invention. This may be especially important for compositions intended for parenteral use, such as injectable compositions. Solubilizers may also be added to increase the solubility of hydrophilic drugs and/or other components such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and its isomers, glycerin, pentaerythritol, sorbose Alcohol, mannitol, diethylene glycol monoethyl ether (transcutol), dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclic Dextrin and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of from about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethyl Acetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, octanoic acid Ethyl ester, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β- Butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, caprylic monoglyceride, diethylene glycol monoethyl ether and water.

Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxy Propyl methylcellulose, hydroxypropyl cyclodextrin, ethyl alcohol, macrogol 200-100, tetrahydrofurfuryl alcohol polyglycol ether, diethylene glycol monoethyl ether, propylene glycol, and dimethylisosorbide. Particularly preferred solubilizers include sorbitol, glycerin, triacetin, ethanol, PEG-400, tetrahydrofurfuryl alcohol polyglycol ether, and propylene glycol.

The amount of solubilizing agent that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be readily determined by one skilled in the art. In some cases, it may be advantageous to include an amount of solubilizing agent well in excess of a biologically acceptable amount, e.g. to maximize drug concentration, to be removed using conventional techniques (e.g. distillation or evaporation) prior to providing the composition to a subject. Excess solubilizer. Thus, if present, the solubilizing agent may be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of the drug and other excipients. Very small amounts of solubilizers, such as 5%>, 2%>, 1% or even less, can also be used if desired. Typically, the solubilizing agent may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.

The composition may also contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, Colorants, flavor enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

In addition, acids or bases may be incorporated into the compositions to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate , synthetic hydrocalcite, aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) wait. Furthermore suitable bases are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, Acids, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, brosylic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid , succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate, and monobasic sodium phosphate may also be used. When the base is a salt, the cation may be any suitable and pharmaceutically acceptable cation, such as ammonium, alkali metal, alkaline earth metal, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, boric, phosphoric, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid , hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, Tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

Pharmaceutical composition for injection .

In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains the compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the agents in the compositions are as described herein.

Forms that may be incorporated into the novel compositions of the present invention for administration by injection include those with sesame oil, corn oil, cottonseed oil or peanut oil as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous or oily suspensions or emulsions.

Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin to maintain the desired particle size in the case of dispersions and by the use of surfactants. Prevention of the action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound of this invention in the required amount in an appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques, which yield the active ingredient plus any other desired ingredient from a previously sterile-filtered solution thereof. of powder.

Pharmaceutical compositions for topical (eg transdermal) delivery .

In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

The compositions of the present invention may be formulated as preparations in solid, semi-solid or liquid form suitable for topical or topical application, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, slurries , ointments, solutions, oils, pastes, suppositories, sprays, lotions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities will provide areas that will be exposed to the active ingredient for extended periods of time. In contrast, solution formulations allow for more direct exposure of the active ingredient to the chosen area.

The pharmaceutical composition may also comprise suitable solid or gel phase carriers or excipients that allow for increased penetration of the therapeutic molecule across the stratum corneum penetration barrier of the skin or facilitate delivery of the therapeutic molecule for penetration across the stratum corneum of the skin barrier compound. There are many such penetration enhancing molecules known to those trained in the field of topical formulations.

Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glyceryl monolaurate, sulfoxides, terpenes (such as menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycol.

Another exemplary formulation for use in the methods of the invention uses a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the invention in controlled amounts, with or without another pharmaceutical agent.

The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, eg, US Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

Pharmaceutical composition for inhalation .

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

other pharmaceutical compositions .

The pharmaceutical composition may also be composed of a composition described herein and one or more pharmaceutically acceptable drugs suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. Excipient preparation. The preparation of such pharmaceutical compositions is well known in the art. See, eg, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds. Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Edited by Katzung, Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, ed., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd Edition (The Pharmaceutical Press, London, 1999); all of which are hereby incorporated by reference in their entirety.

Administration of a compound or pharmaceutical composition of the invention can be accomplished by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, Delivered locally by catheter or stent or by inhalation. Compounds can also be administered intralipidally or intrathecally.

In some embodiments, a compound or pharmaceutical composition of the invention is administered by intravenous injection.

The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. However, effective dosages are in the range of about 0.001 to about 100 mg/kg body weight/day, preferably about 1 to about 35 mg/kg/day, in single or divided administration. For a 70 kg human this would correspond to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some cases, dose levels below the lower limit of the above range may be adequate, while in other cases larger doses may be used without causing any harmful side effects, e.g. by dividing such a large dose into several smaller doses to Apply throughout the day.

In some embodiments, compounds of the invention are administered in a single dose.

Typically, such administration will be by injection, such as intravenous injection, for rapid introduction of the agent. However, other routes can be used as appropriate. A single dose of a compound of the invention may also be used in the treatment of acute conditions.

In some embodiments, the compounds of the invention are administered in multiple doses. Administration may be about once, twice, three, four, five, six, or more than six times per day. Dosing can be about monthly, biweekly, weekly, or every other day. In another embodiment, the compound of the invention and another agent are administered together from about once a day to about 6 times a day. In another embodiment, the administration of the compounds and agents of the invention lasts for less than about 7 days. In yet another embodiment, the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some instances, continuous dosing is achieved and maintained as needed.

Administration of the compounds of the invention can be continued as needed. In some embodiments, a compound of the invention is administered over 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically on a sustained basis, eg, for the treatment of chronic effects.

An effective amount of a compound of the present invention may be administered in single or multiple doses by any accepted mode of administration of agents of similar utility, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenous, intraperitoneal , parenterally, intramuscularly, subcutaneously, orally, topically or as an inhalant.

Compositions of the invention may also be delivered via impregnated or coated devices such as stents or arterially inserted cylindrical polymers. For example, such methods of administration can help prevent or ameliorate restenosis following procedures such as balloon angioplasty. Without being bound by theory, the compounds of the invention slow or inhibit smooth muscle cell migration and proliferation in arterial walls leading to restenosis. The compounds of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from a graft, or from a covering or sheath of a stent. In some embodiments, a compound of the invention is mixed with a matrix. This matrix can be a polymer matrix and can be used to bind the compound to the scaffold. Polymer matrices suitable for such applications include, for example, lactone polyesters or copolyesters such as polylactide, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes , poly(ether-ester) copolymers (such as PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate polymers or copolymers (such as polyhydroxyethylmethacrylate , polyvinylpyrrolidone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degrading or may degrade over time, releasing the compound or compounds. The compounds of the present invention can be applied to the surface of the stent by various methods such as dipping/spinning, spraying, dipping and/or brushing. The compound can be applied in a solvent and the solvent can be allowed to evaporate, forming a layer of the compound on the stent. Alternatively, the compound may be located in the body of the stent or graft, eg in microchannels or pores. When implanted, the compound diffuses out of the stent body to contact the artery wall. Such scaffolds can be prepared by dipping a scaffold fabricated to contain such micropores or microchannels in a solution of a compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the stent surface can be removed via an additional brief solvent wash. In other embodiments, compounds of the invention can be covalently attached to a stent or graft. Covalent linkers may be used, which degrade in vivo, resulting in release of the compound of the invention. Any biolabile linkage can be used for such purposes, such as ester, amide or anhydride linkages. Compounds of the invention may also be administered intravascularly from balloons used during angioplasty. Extravascular administration of the compounds to reduce restenosis can also be performed via the pericardium or via peripheral application of formulations of the invention.

A variety of stent devices that can be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Patent No. 5,451,233; U.S. Patent No. 5,040,548; U.S. Patent No. 5,061,273; U.S. Patent No. US Patent No. 5,292,331; US Patent No. 5,674,278; US Patent No. 3,657,744; US Patent No. 4,739,762; ; U.S. Patent No. 6,344,053.

The compounds of the invention may be administered in dosages. It is known in the art that due to interindividual variability in compound pharmacokinetics, individualization of dosing regimens is necessary for optimal therapy. Dosages of compounds of the invention may be determined by routine experimentation in light of the present disclosure.

When a compound of the invention is administered in a composition comprising one or more agents that have a shorter half-life than the compound of the invention, the unit dosage forms of the agents and the compound of the invention can be adjusted accordingly.

For example, the subject pharmaceutical composition may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions; for parenteral injection, such as sterile solutions, suspensions or emulsions; A form suitable for topical administration, such as an ointment or cream; or a form suitable for rectal administration, such as a suppository. The pharmaceutical compositions may be in unit dosage form suitable for single administration of precise dosages. Pharmaceutical compositions will comprise conventional pharmaceutical carriers or excipients and the compound according to the invention as active ingredient. Furthermore, it may include other drugs or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered if necessary.

Instructions

The methods generally comprise administering to a subject a therapeutically effective amount of a compound of the invention. Therapeutically effective amounts of the subject combinations of compounds may vary depending on the intended application (in vitro or in vivo) or on the subject and condition being treated, such as the subject's weight and age, severity of the condition, mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that induce a specific response in target cells, such as decreased proliferation or down-regulation of activity of a target protein. The specific dosage will vary depending on the particular compound chosen, the administration regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system with which it is carried.

As used herein, the term " _IC50 " refers to the half maximal inhibitory concentration of an inhibitor in inhibiting a biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is required to inhibit a given biological process (or process component, i.e. enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC or IC50). EC50 refers to the plasma concentration required to obtain >50% of the maximum effect in vivo.

In some embodiments, the subject methods use an MCL-1 inhibitor with an IC50 value of about or less than a predetermined value, as determined in an in vitro assay. In some embodiments, the MCL-1 inhibitor is present at about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or Lower, 50nM or lower, 60nM or lower, 70nM or lower, 80nM or lower, 90nM or lower, 100nM or lower, 120nM or lower, 140nM or lower, 150nM or lower, 160nM or Lower, 170nM or lower, 180nM or lower, 190nM or lower, 200nM or lower, 225nM or lower, 250nM or lower, 275nM or lower, 300nM or lower, 325nM or lower, 350nM or Lower, 375nM or lower, 400nM or lower, 425nM or lower, 450nM or lower, 475nM or lower, 500nM or lower, 550nM or lower, 600nM or lower, 650nM or lower, 700nM or Lower, 750nM or lower, 800nM or lower, 850nM or lower, 900nM or lower, 950nM or lower, 1μM or lower, 1.1μM or lower, 1.2μM or lower, 1.3μM or lower , 1.4 μM or lower, 1.5 μM or lower, 1.6 μM or lower, 1.7 μM or lower, 1.8 μM or lower, 1.9 μM or lower, 2 μM or lower, 5 μM or lower, 10 μM or lower Low, 15 μM or lower, 20 μM or lower, 25 μM or lower, 30 μM or lower, 40 μM or lower, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or lower ( or an IC50 value defined by any two of the above numbers up to and including their range) inhibits MCL-1a.

In some embodiments, the MCL-1 inhibitor selectively inhibits MCL-1a with an IC50 value that is at least 2, 3, 4, 5 less than its IC50 value for one, two or three other MCL-1s , 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times (or a number defined by and including any two of the above numbers).

In some embodiments, the MCL-1 inhibitor selectively inhibits MCL-1a with an IC50 value of less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM 、120nM、140nM、150nM、160nM、170nM、180nM、190nM、200nM、225nM、250nM、275nM、300nM、325nM、350nM、375nM、400nM、425nM、450nM、475nM、500nM、550nM、600nM、650nM、700nM、750nM , 800nM, 850nM, 900nM, 950nM, 1μM, 1.1μM, 1.2μM, 1.3μM, 1.4μM, 1.5μM, 1.6μM, 1.7μM, 1.8μM, 1.9μM, 2μM, 5μM, 10μM, 15μM, 20μM, 25μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM or 500 μM (or within the range defined by any two of the above numbers and including them), and the IC50 value compared to its IC50 values for one, two, or three other MCL-1s that are at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times (or a number within a range defined by and including any two of the above numbers).

The subject methods can be used to treat disease conditions associated with MCL-1. Any disease condition that results directly or indirectly from abnormal activity or expression levels of MCL-1 may be the desired disease condition.

Different disease states associated with MCL-1 have been reported. MCL-1 is associated with, for example, autoimmune diseases, neurodegeneration (such as Parkinson's disease, Alzheimer's disease and ischemia), inflammatory diseases, viral infections and cancers such as colon cancer, breast cancer, small cell lung cancer, non-small cell Lung, bladder, ovarian, prostate, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentigo melanoma, acral hidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute Lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic leukemia, acute myeloid leukemia, acute myeloid leukemia, acute protozoan Myeloid leukemia, ameloblastoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancers, AIDS Associated lymphoma, acinar soft tissue sarcoma, ameloblastic fibroma, anal carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix Carcinoma, astrocytoma, atypical teratoma rhabdoid tumor, basal cell carcinoma, basaloid carcinoma, B cell leukemia, B cell lymphoma, Bellini duct carcinoma, biliary tract carcinoma, bladder carcinoma , blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, Brown tumor, Burkitt lymphoma Burkitt's lymphoma, cancer of unknown primary site, carcinoid tumor, carcinoma, carcinoma in situ, penile carcinoma, carcinoma of unknown primary site, carcinosarcoma, Castleman's Disease, CNS Nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic mono Nuclear Cell Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Chronic Neutrophil Leukemia, Clear Cell Tumor, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Degos Degos disease, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, Endometrial cancer, endometrial uterine cancer, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymal blastoma, ependymoma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer , Olfactory neuroblastoma, Ewing tumor family, Ewing family sarcoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, extramammary Paget's disease, fallopian tube cancer, fetal Middle fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastric Intestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell Glioma, germ cell tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis, glomus tumor, glomus tumor melanoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, head and neck cancer, heart cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), hemangioblastoma, Angiopericytoma, angiosarcoma, hematological malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast-ovarian cancer syndrome, Hodgkin's lymphoma, Hodgkin's lymphoma, hypopharyngeal carcinoma, Hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, Kaposi's sarcoma, renal carcinoma, hilar cholangiocarcinoma ( Klatskin tumor), Krukenberg tumor, laryngeal cancer, laryngeal cancer, lentigo maligna melanoma, leukemia, lip and oral cancer, liposarcoma, lung cancer, luteinoma, lymphangioma, lymphangiosarcoma, Lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath malignant rhabdoid tumor, malignant salamander tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mast cell disease, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid carcinoma, medulloblastoma, medulloblastoma medulloblastoma, medulloblastoma, melanoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma, metastatic squamous carcinoma of the neck with occult primary, metastatic urothelial carcinoma, mixed Mu Leuteroma, monocytic leukemia, oral cancer, mucinous neoplasms, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma, mycosis fungoides, mycosis fungoides, myelodysplastic disease, myeloid Dysplastic syndrome, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity carcinoma, nasopharyngeal carcinoma, nasopharyngeal carcinoma, neoplasm, schwannoma, neuroblastoma, neuroblastoma, neuroblastoma Fibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular tumor, oligoastrocytoma, oligodendrocyte Glioblastoma, oncocytoma, optic nerve sheath meningioma, oral cavity cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential Tumors, Paget's disease of the breast, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer , perivascular epithelioid cell tumor, pharyngeal carcinoma, pheochromocytoma, intermediately differentiated pineal solid tumor, pinealoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary Blastoma, multiple embryonal tumor, precursor T-lymphoblastic lymphoma, primary Central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal carcinoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, Renal cell carcinoma, respiratory cancer involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, Richter's transformation, sacrococcygeal teratoma, salivary gland carcinoma, sarcoma, nerve Schwannomatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord stromal tumor, Sezary syndrome (Sezary Syndrome), signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small bowel cancer, soft tissue sarcoma, somatostatin tumor, soot wart, spinal cord tumor, Spinal tumors, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, advanced lymphoma, testicular cancer, sheath cancer, laryngeal cancer, thymus cancer, thymoma, thyroid cancer , transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, ureteral carcinoma, urethral carcinoma, urogenital neoplasm, uterine sarcoma, uveal melanoma, vaginal carcinoma, Verner Morrison syndrome, Verrucous carcinoma, visual pathway glioma, vulvar carcinoma, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

In some embodiments, the method is used to treat a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and Scleroderma, diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and cancer of the ovary, breast, lung, pancreas, prostate carcinoma, colon carcinoma and epidermoid carcinoma.

In other embodiments, the method is for treating a disease selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, the method is used to treat a disease selected from the group consisting of: leukemia such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloid Dysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myeloid hyperplasia Dysmorphic syndrome (MDS) or epidermoid carcinoma.

The compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered alone or in combination with medical therapies for the treatment of any such disease. Medical therapies include, for example, surgery and radiation therapy (eg, gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, whole body radioisotopes).

In other aspects, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, may be administered alone or in combination with one or more other agents to treat any of the described diseases.

In other methods, the disclosed compounds and pharmaceutical compositions comprising them may be administered in combination with agonists of nuclear receptor agents.

In other methods, the disclosed compounds and pharmaceutical compositions comprising them may be administered in combination with antagonists of nuclear receptor agents.

In other methods, the compounds of the disclosure and pharmaceutical compositions comprising them can be administered in combination with antiproliferative agents.

combination therapy

For the treatment of cancer and other proliferative diseases, the compounds of the invention may be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors or other antiproliferative agents. The compounds of the invention may also be used in combination with medical therapies such as surgery or radiation therapy, eg gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy and systemic radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol ( allopurinol), all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, shellac Bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, oral busulfan (busulfan oral), calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil ), cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin , dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, right Dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erubicin Erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, non Filgrastim, floxuridine, fludarabine, fluorouracil racil), fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate acetate), ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate ( leuprolide acetate), levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methylamine pterin (methotrexate), methoxsalen (methoxsalen), mitomycin C (mitomycin C), mitotane (mitotane), mitoxantrone (mitoxantrone), phenylpropionate (nandrolone phenpropionate), natrolone Nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab ), pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, Pukamycin plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib ( sorafenib), streptozocin (streptozocin), sunitinib (sunitinib), sunitinib maleate ( sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa (thiotepa), topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard ), valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate.

In some embodiments, compounds of the invention may be used in combination with therapeutic agents that target epigenetic modulators. Examples of epigenetic modulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone Sirtuin inhibitors, histone acetylase inhibitors and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, for example, vorinostat. Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs), such as PRMT5, PRMT1 and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

For the treatment of cancer and other proliferative diseases, the compounds of the invention can be used in combination with targeted therapies, including JAK kinase inhibitors (such as ruxolitinib), PI3 kinase inhibitors (including PI3K-delta selective and broad-spectrum PI3K inhibition agents), MEK inhibitors, cyclin-dependent kinase inhibitors (including CDK4/6 inhibitors and CDK9 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (such as bortezomib, carfilzomib ), HDAC inhibitors (e.g. panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromide and extra terminal family member (BET) inhibitors, BTK inhibitors (e.g. Ibrutinib, acalabrutinib), BCL2 inhibitors (eg, venetoclax), dual BCL2 family inhibitors (eg, BCL2/BCLxL), PARP inhibitors, FLT3 inhibitors or LSD1 inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of an immune checkpoint molecule is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL) and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

For the treatment of autoimmune or inflammatory conditions, the compounds of the present invention may be combined with corticosteroids such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone or Flumetholone was administered in combination.

利美索龙(rimexolone)(AL-2178、Vexol、Alcon)或环孢菌素

组合施用。For the treatment of autoimmune or inflammatory conditions, the compounds of the present invention can be combined with immunosuppressants such as fluocinolone acetonide (fluocinolone acetonide)

rimexolone (AL-2178, Vexol, Alcon) or cyclosporine

Administer in combination.

synthesis

The compounds of the invention can be prepared according to a number of preparation routes known in the literature. The following schemes provide general guidance in connection with the preparation of compounds of the invention. Those skilled in the art will appreciate that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Exemplary synthetic methods for preparing compounds of the invention are provided in the schemes below.

Intermediate 1

-3,1'-四氢化萘]-7-磺酰胺6'-Chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

Step 1: 6'-Chlorospiro[oxirane-2,1'-tetralin]

To a solution of 6-chlorotetralin-1-one (10.0 g, 55.3 mmol) in DMSO (100 mL) was added trimethylsulfonium iodide (12.4 g, 60.9 mmol) and potassium hydroxide (6.21 g, 110 mmol) , and the mixture was stirred at 25°C for 24 hours. The mixture was added to ice water ₍ 500 mL), extracted with MTBE (400 mL x 3), the organic phases were combined, washed with brine (500 mL x 2), dried over _Na2SO4 , filtered and concentrated in vacuo to give 6'-chloro Spiro[oxirane-2,1'-tetralin] (10.0 g, 51.3 mmol, 92% yield).

Step 2: 6-Chlorotetralin-1-carbaldehyde

To a solution of 6'-chlorospiro[oxirane-2,1'-tetralin] (10.0 g, 51.3 mmol) in THF (160 mL) was added boron trifluoride etherate at -8°C (364mg, 2.57mmol), the solution was stirred at -8°C for 10 minutes. The reaction was quenched with saturated _NaHCO3 (200 mL) at -8 °C, the aqueous phase was extracted with MTBE (400 mL x 2), the organic phases were combined, washed with brine (400 mL), dried over _Na2SO4 , filtered and _concentrated in vacuo to give 6-Chlorotetralin-1-carbaldehyde (11.40 g, 70% purity, 40.995 mmol, 79% yield).

Step 3: [6-Chloro-1-(hydroxymethyl)tetralin-1-yl]methanol

To a solution of 6-chlorotetralin-1-carbaldehyde (11.4 g, 70% purity, 41 mmol) in 2-(2-hydroxyethoxy)ethanol (80 mL, 41 mmol) was added paraformaldehyde (56 mL, 41 mmol) ), then potassium hydroxide (56 mL, 41 mmol) was added to the mixture at 5°C. The reaction mixture was stirred at 45°C for 1 hour. Brine (250 mL) was added to the reaction mixture, extracted with DCM (300 mL×3), the organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo, the residue was subjected to silica gel column chromatography (PE:EA=1.5:1 ) to give [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol (11.2 g, 75% purity, 90% yield). ¹ H NMR (400MHz, CDCl ₃ ): δ7.31-7.34(m,2H),7.11-7.14(m,2H),3.87-3.91(m,2H),3.72-3.76(m,2H),2.73- 2.76 (m, 2H), 2.11-2.15 (m, 2H), 1.89-1.92 (m, 2H), 1.79-1.83 (m, 2H).

Step 4: 6-Chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate

To a solution of [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol (11.2 g, 37 mmol) in DCM (150 mL) was added benzoyl chloride (6.26 g, 44 mmol) at 0 °C ), followed by the dropwise addition of DIPEA (7.4 mL, 44 mmol). The mixture was stirred at 25°C for 16 hours. DCM (150 mL) was added to the mixture, washed with saturated NH ₄ Cl (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo, the residue was subjected to silica gel column chromatography (PE:EA=9: 1) Purification to obtain 11.65 g of racemic product. ¹ H NMR (400MHz, CDCl ₃ ): δ8.00-8.02(m, 2H), 7.57-7.61(m, 1H), 7.44-7.48(m, 3H), 7.14-7.16(m, 2H), 4.48( s, 2H), 3.74-3.82 (m, 2H), 2.78-2.81 (m, 2H), 1.83-1.95 (m, 4H).

Step 5: (6-Chloro-1-formyl-tetralin-1-yl)methyl benzoate

To a solution of [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate (1.48 g, 4.47 mmol) in DCM (25 mL) was added Dess-Martin at 0 °C Dess-Martin periodinane (2.84 g, 6.7 mmol), and the mixture was stirred at 25°C for 1 hour. A 1:1 mixture (100 mL) of 10% Na ₂ S ₂ O ₃ /saturated NaHCO ₃ solution was added to the reaction mixture. The mixture was extracted with DCM (100 mL x 2). The combined organic phases were washed with brine (15 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by FC on a silica gel column to give (6-chloro-1-formyl-tetralin-1-yl)methyl benzoate (1.24 g, 84% yield). ¹ H NMR (400MHz, CDCl ₃ ): δ9.61(s, 1H), 7.94-7.96(m, 2H), 7.54-7.58(m, 1H), 7.41-7.45(m, 2H), 7.15-7.21( m,3H),4.75(d,J=11.6Hz,1H),4.55(d,J=11.6Hz,1H),2.81-2.85(m,2H),2.19-2.23(m,1H),2.00-2.06 (m,1H),1.89-1.95(m,2H).

Step 6: [6-Chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol

To a solution of (6-chloro-1-formyl-tetralin-1-yl)methyl benzoate (1.24 g, 3.77 mmol) in methanol (25 mL) was added p-TsOH H ₂ O (35 mg, 0.19 mmol) and trimethyl orthoformate (1.2 g, 11.3 mmol). The mixture was stirred at 70°C for 4 hours, then concentrated to 50% volume. The residue was diluted with THF (25 mL) and 1 N NaOH (25 mL) was added. The resulting reaction mixture was stirred at 40°C for 4 hours. Solvent was removed. The residue was extracted with EA (20 mL x 3). The combined organic layers were washed with 1N NaOH (50 mL) and brine (100 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by FC on a silica gel column (PE:EA=9:1) to give [6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (0.98g, 96% Yield). ¹ H NMR (400MHz, CDCl ₃ ): δ7.35(d, J=8.4Hz, 1H), 7.10-7.13(m, 2H), 4.49(s, 1H), 3.90(dd, J=3.8, 11.2Hz ,1H),3.53(dd,J＝8.4,11.2Hz,1H),3.46(s,3H),3.33(s,3H),2.68-2.76(m,2H),1.99-2.06(m,1H), 1.89-1.96 (m, 1H), 1.70-1.86 (m, 2H).

Step 7: 4-[[6-Chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]-3-nitro-benzenesulfonamide

To a mixture containing [6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (818 mg, 3.02 mmol) and potassium tert-butoxide (779 mg, 6.94 mmol) under _N A 100 mL flask with septum was charged with THF (22 mL) to give a tan solution. The solution was stirred at 0 °C for 5 min, then a solution of 4-fluoro-3-nitrobenzenesulfonamide (731 mg, 3.32 mmol) in THF (4 mL) was added at 0 °C over 8 min. The reaction was stirred at 0 °C for 20 minutes. The reaction mixture was quenched with saturated _NH4Cl (10 mL). The reaction mixture was diluted with water (80 mL) and saturated _NH4Cl (10 mL), and extracted with EtOAc (100 mL). The organic layer was washed with water (70 mL) and saturated NH ₄ Cl (10 mL) and brine (50 mL). The aqueous layers were combined and back extracted with EtOAc (60 mL), washed with water (60 mL) and brine (30 mL). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to give 4 _- [[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxyl as a yellow foam Di]-3-nitro-benzenesulfonamide (1.52 g) and used directly in the next reaction without further purification. R _f = 0.36 (1:1 hexane:EtOAc); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.28 (d, J = 2.3 Hz, 1H), 8.01 (dd, J = 2.4, 8.9 Hz, 1H), 7.60(dd, J＝8.7, 16.3Hz, 2H), 7.50(s, 2H), 7.19–7.11(m, 2H), 4.63(s, 1H), 4.38–4.26(m, 2H), 3.38 (s,3H),3.29(s,3H),2.70(d,J＝6.2Hz,2H),2.04–1.94(m,1H),1.90–1.79(m,2H),1.77–1.67(m,1H ).

Step 8: 4-[(6-Chloro-1-formyl-tetralin-1-yl)methoxy]-3-nitro-benzenesulfonamide

Amberlyst 16 wet catalyst was rinsed with acetone and dried under high vacuum before use. The crude 4-[[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]-3 _- nitro-benzenesulfonamide (1.42 g , 3.02 mmol) and preconditioned Amberlyst 16 wet (1 g, about 7.44 mmol) into a 500 mL RBF with septum charged with acetone (30 mL). The reaction mixture was heated at 50 °C for 2 hours, filtered through cotton and rinsed with DCM. The filtrate was concentrated under reduced pressure to give 4-[(6-chloro-1-formyl-tetralin-1-yl)methoxy]-3-nitro-benzenesulfonamide (1.7 g) as an orange/brown oil, It was directly used in the next reaction without further purification. R _f = 0.31 (1:1 hexane:EtOAc); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.65 (s, 1 H), 8.27 (d, J = 2.4 Hz, 1 H), 8.03 (dd, J=2.4,8.9Hz,1H),7.63(d,J=9.0Hz,1H),7.50(s,2H),7.35–7.29(m,2H),7.26(dd,J=2.4,8.4Hz,1H ), 4.77(d, J=9.6Hz, 1H), 4.47(d, J=9.6Hz, 1H), 2.78(t, J=6.3Hz, 2H), 2.19(ddd, J=3.0, 8.9, 13.2Hz , 1H), 1.99 (ddd, J=2.8, 8.1, 13.5Hz, 1H), 1.89–1.80 (m, 1H), 1.80–1.70 (m, 1H).

-3,1'-四氢化萘]-7-磺酰胺Step 9: 6'-Chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

-3,1'-四氢化萘]-7-磺酰胺。R_f＝0.24(1:1EtOAc/己烷)；关于C₁₈H₁₈ClN₂O₃S的LCMS计算值(M+H)⁺:m/z＝377.07/379.07；实验值：377.0/379.0。To a solution of crude 4-[(6-chloro-1-formyl-tetralin-1-yl)methoxy]-3-nitro-benzenesulfonamide (assumed 3.02 mmol) in acetic acid (50 mL) Charge iron powder (1.69 g, 30.2 mmol). The mixture was heated at 70°C for 3 hours. The mixture was charged with Celite, diluted with DCM (50 mL), filtered through a plug of Celite, and rinsed with DCM to give crude 6'-chlorospiro[2H-1,5-benzoxazepine

-3,1'-tetrahydronaphthalene]-7-sulfonamide. _Rf = 0.24 (1: _{1 EtOAc} /Hex); LCMS calcd for _{C18H18ClN2O3S} (M+ _H ) ⁺ : m/z = 377.07/379.07; found: 377.0/379.0.

-3,1'-四氢化萘]-7-磺酰胺(1.24g，2.61mmol，86％产率)。R_f＝0.45(1:1EtOAc/己烷)。关于C₁₈H₂₀ClN₂O₃S的LCMS计算值(M+H)⁺:m/z＝379.09/379.08；实验值：379.0/381.0；¹H NMR(500MHz,DMSO-d₆)δ7.81(d,J＝8.5Hz,1H),7.26(dd,J＝2.4,8.5Hz,1H),7.18(dd,J＝2.3,15.2Hz,2H),7.13(s,2H),7.02(dd,J＝2.3,8.4Hz,1H),6.92(d,J＝8.4Hz,1H),6.20(t,J＝4.1Hz,1H),4.08(q,J＝12.2Hz,2H),3.23(dd,J＝4.7,13.7Hz,1H),2.77–2.65(m,2H),1.87–1.66(m,3H),1.55(ddd,J＝2.9,9.7,12.7Hz,1H)。The filtrate was concentrated under reduced pressure, dissolved in DCM (30 mL), cooled to 0 °C, and sodium triacetoxyborohydride (1.99 g, 9.44 mmol) was charged over 1 min. The reaction mixture was stirred at 0 °C for 1 min, then at room temperature for 80 min. The reaction mixture was quenched with 10% citric acid (30 mL), diluted with water (30 mL), and extracted with EtOAc (125 mL). The organic layer was washed with 10% citric acid (10 mL) and water (40 mL), washed with brine (2 _x 40 mL), dried over _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure to give 6'-chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine as a light tan foam

-3,1'-tetralin]-7-sulfonamide (1.24 g, 2.61 mmol, 86% yield). _Rf = 0.45 (1:1 EtOAc/Hex). LCMS calculated for C ₁₈ H ₂₀ ClN ₂ O ₃ S (M+H) ⁺ : m/z = 379.09/379.08; found: 379.0/381.0; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ7.81 (d,J=8.5Hz,1H),7.26(dd,J=2.4,8.5Hz,1H),7.18(dd,J=2.3,15.2Hz,2H),7.13(s,2H),7.02(dd, J＝2.3,8.4Hz, 1H), 6.92(d, J＝8.4Hz, 1H), 6.20(t, J＝4.1Hz, 1H), 4.08(q, J＝12.2Hz, 2H), 3.23(dd, J=4.7, 13.7Hz, 1H), 2.77-2.65(m, 2H), 1.87-1.66(m, 3H), 1.55(ddd, J=2.9, 9.7, 12.7Hz, 1H).

Intermediate 2

-3,1'-四氢化萘]-7-磺酰胺(3S)-6'-Chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

Step 1: 4-Fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide

To a cooled (-35 °C) solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added triethylamine (3.13 mL, 22.46 mmol), followed by 30 min A solution of bis-(4-methoxybenzyl)amine (4.97 mL, 20.7 mmol) in THF (50 mL) was added while maintaining the temperature at -35°C. After the addition was complete, the temperature was allowed to slowly increase to 0°C over 1 hour, and the mixture was stirred at 0°C for an additional 1 hour. The mixture was neutralized with 1N HCl to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with 1N HCl (10 mL), 7.5% aqueous NaHCO3 (20 mL) and brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 minutes and allowed to stand at room temperature for 1 hour. The mixture was filtered and washed with hexanes to give the desired title product (6.85g) without further purification. The mother liquor was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexanes were added following the above procedure to give an additional 0.51 g of the title product. The total product 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained was 7.36 g (78%). ¹ H NMR (400MHz,DMSO-d ₆ ):δ8.18-8.23(m,2H),7.75-7.79(q,1H),7.08(d,4H),6.81(d,4H),4.31(s, 4H), 3.71(s, 6H). ¹⁹ F NMR (376 MHz, DMSO-d6): δ-112.54 (s, 1F). LCMS calculated _{for C22H22FN2O6S} (M+H) ⁺ : _m /z = _461.11 ; found: 461.1.

Step 2: [(1S)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate and [(1R)-6-chloro-1-(hydroxymethyl)benzoate Tetrahydronaphthalen-1-yl]methyl ester

The racemic product 6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate (Intermediate 1, step 4) was separated by a Waters-SFC80 instrument under separation conditions: Column: AD- H (2.5×25cm, 10um); mobile phase A: supercritical CO ₂ , mobile phase B: EtOH, A:B=80/20, 60mL/min; cycle time: 15 minutes; sample preparation: ethanol; injection volume: 0.8 mL; detector wavelength: 214 nm; column temperature: 25°C; back pressure: 100 bar. The isolated product was assayed by chiral HPLC. Chiral HPLC conditions: chiral column: AD-H, 5um, 4.6mm×250mm (Daicel); mobile phase: supercritical CO ₂ /EtOH/DEA 70/30/0.06; flow rate: 2.0mL/min and running time: In 12 minutes, [(1S)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate (P1, RT=4.952 minutes) and [(1R)-6 -Chloro-1-(hydroxymethyl)tetralin-1-yl]methyl ester (P2, retention time = 6.410 min). ¹ H NMR (400MHz, CDCl ₃ ): δ8.00-8.02(m, 2H), 7.57-7.61(m, 1H), 7.44-7.48(m, 3H), 7.14-7.16(m, 2H), 4.48( s, 2H), 3.74-3.82 (m, 2H), 2.78-2.81 (m, 2H), 1.83-1.95 (m, 4H).

Step 3: [(1R)-6-Chloro-1-formyl-tetralin-1-yl]methyl benzoate

Using a procedure similar to that described for Intermediate 1, [(1S)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate was used in Step 5 (Step 2, P1 ) in place of racemic [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate to prepare this compound. ¹ H NMR (400MHz, CDCl ₃ ): δ9.61(s, 1H), 7.94-7.96(m, 2H), 7.55-7.58(m, 1H), 7.41-7.45(m, 2H), 7.15-7.20( m,3H),4.73-4.76(d,1H),4.53-4.56(d,1H),2.82-2.85(m,2H),2.20-2.26(m,1H),2.01-2.07(m,1H), 1.90-1.96(m,2H).

Step 4: [(1R)-6-Chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol

Method A: Using a procedure similar to that described for Intermediate 1, [(1R)-6-chloro-1-formyl-tetralin-1-yl]methyl benzoate was used in step 6 instead of racemic (6-Chloro-1-formyl-tetralin-1-yl)methyl benzoate to prepare this compound. ¹ H NMR (400MHz, CDCl ₃ +D ₂ O): δ7.34-7.36(m,1H),7.10-7.12(m,2H),4.49(s,1H),3.89-3.91(d,1H), 3.50-3.53(m,1H),3.46(s,3H),3.33(s,3H),2.68-2.76(m,2H),1.99-2.06(m,1H),1.89-1.96(m,1H), 1.70-1.86(m,2H).

Method B: Racemic (6-Chloro-1-formyl-tetrahydronaphthalen-1-yl)methyl benzoate (Intermediate 1 step 6) was passed through a chiral column on a Berger MG2 preparative SFC instrument under separation conditions Lower separation: column: ChiralPak IC (2×25cm); mobile phase A: i-PrOH, mobile phase B: supercritical CO ₂ , A:B=1/3, 60mL/min; cycle time (running time): 5 minute injection interval; sample preparation: 20 mg/mL iPrOH/DCM; injection volume: 0.5 mL; detector wavelength: 220 nm; column temperature: 30 °C; back pressure: 100 bar. The isolated products were assayed by chiral HPLC on a Berger analytical SFC. Chiral HPLC conditions: chiral column: ChiralPak IC, 5um, 4.6mm×250mm (Daicel); mobile phase: i-PrOH/supercritical CO ₂ /EtOH 1/3; flow rate: 3.0mL/min and run time: 7 minutes; detector wavelength (UV length): 220nm, 254nm and 280nm; column temperature: 30°C; Naphthalen-1-yl]methanol (P1, RT=1.96 min) and [(1R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (P2, RT = 2.69 minutes).

Step 5: N,N-Bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-(dimethoxymethyl)- Tetralin-1-yl]methoxy]benzenesulfonamide

To [(1R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (2.96 g, 10.93 mmol, P2) in THF at -40 °C under _N2 atmosphere LiHMDS (11.5mL, 11.4mmol) was added dropwise to a solution in (50mL), the solution was stirred at -40°C for 5 minutes, and then 4-fluoro-N,N-bis[(4-methoxyphenyl) A solution of Methyl]-3-nitro-benzenesulfonamide (7.55 g, 16.4 mmol) (Step 1) in THF (30 mL). The solution was stirred at -40°C for 5 minutes, and then the mixture was stirred at room temperature for 1 hour. The reaction was cooled with an ice-water bath and quenched with saturated aqueous _NH4Cl (100 mL). The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with saturated _NH4Cl solution and brine, dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate (EA) and petroleum ether (PE) to give N,N-bis[(4-methoxyphenyl)methyl]-3-nitro - 4-[[(1R)-6-Chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]benzenesulfonamide (6.41 g, 82% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.06-8.07(m,1H),7.97-8.00(m,1H),7.60-7.62(m,1H),7.49-7.51(m,1H), 7.14-7.17(m,2H),6.99-7.07(m,4H),6.77-6.79(m,4H),4.62(s,1H),4.27-4.36(m,2H),4.24(s,4H), 3.70(s,6H),3.39(s,3H),3.30(s,3H),2.68-2.71(m,2H),1.98-2.00(m,1H),1.81-1.85(m,2H),1.71- 1.73(m,1H).

Step 6: N,N-Bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-formyl-tetralin-1- [yl]methoxy]benzenesulfonamide

To N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-(dimethoxymethyl)tetralin -1-yl]methoxy]benzenesulfonamide (6.11 g, 8.59 mmol) in THF (80 mL) and water (20 mL) was added p-TsOH·H ₂ O (3.27 g, 17.18 mmol), and The mixture was stirred at 70°C for 16 hours. The mixture was cooled to 0° C., and saturated aqueous NaHCO ₃ (100 mL) was added. The mixture was extracted with EA (100 mL x 3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA and gave N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6 -Chloro-1-formyl-tetralin-1-yl]methoxy]benzenesulfonamide (6.11 g, 85% purity, 91% yield).

-3,1'-萘]-7-磺酰胺Step 7: (S)-6'-Chloro-N,N-bis(4-methoxybenzyl)-3',4'-dihydro-2H,2'H-spiro[benzo[b][ 1,4] Oxazepine

-3,1'-naphthalene]-7-sulfonamide

-3,1'-萘]-7-磺酰胺(6.11g，70％纯度，86％产率)，其未经进一步纯化即直接用于下一步反应。关于C₃₄H₃₄ClN₂O₅S的LCMS计算值(M+H)⁺：m/z＝617.18；实验值：617.3。To N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-formyl-tetralin-1-yl] To a solution of methoxy]benzenesulfonamide (6.11 g, 7.81 mmol) in ethanol (40 mL) and water (20 mL) was added iron powder (2.18 g, 39 mmol) and NH ₄ Cl (827 mg, 15.6 mmol), and the mixture Stir at 100°C for 3 hours. LCMS showed the reaction was complete. Filter the mixture. H ₂ O (20 mL) was added to the filtrate, extracted with EA (30 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to afford (S)-6'-chloro-N,N-bis(4 _- methoxybenzyl)-3',4'-dihydro -2H,2'H-spiro[benzo[b][1,4]oxazepine

-3,1'-naphthalene]-7-sulfonamide (6.11 g, 70% purity, 86% yield), which was directly used in the next reaction without further purification. LCMS calculated for _{C34H34ClN2O5S} (M+H) ⁺ : _m /z _{= 617.18} ; found: 617.3.

-3,1'-四氢化萘]-7-磺酰胺Step 8: (3S)-6'-Chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

-3,1'-萘]-7-磺酰胺(6.11g，6.73mmol)(来自步骤7的粗产物，70％纯度)于DCM(80mL)中的溶液中分批加入NaBH(OAc)₃(7.14g，33.67mmol)。将混合物在25℃搅拌16小时。LCMS显示反应进行得很好。向反应中加入饱和NaHCO₃水溶液(80mL)，用DCM(100mL×3)萃取，经Na₂SO₄干燥，过滤并减压浓缩。将残余物通过用EA和PE洗脱的硅胶柱快速色谱法纯化，得到(3S)-6'-氯-N,N-双[(4-甲氧基苯基)甲基]螺[4,5-二氢-2H-1,5-苯并氧氮杂

-3,1'-四氢化萘]-7-磺酰胺(2.30g，53％产率)。关于C₃₄H₃₆ClN₂O₅S的LCMS计算值(M+H)⁺:m/z＝619.2；实验值：619.3。¹H NMR(400MHz,DMSO-d₆):δ7.81-7.83(m,1H),7.24-7.28(m,2H),7.17-7.18(m,1H),6.95-7.06(m,6H),6.78-6.80(m,4H),6.20(s,1H),4.15(m,4H),4.08-4.14(m,2H),3.68(s,6H),3.30-3.36(m,1H),3.23-3.27(m,1H),2.71-2.75(m,2H),1.76-1.86(m,3H),1.56-1.61(m,1H)。To (S)-6'-chloro-N,N-bis(4-methoxybenzyl)-3',4'-dihydro-2H,2'H-spiro[benzo[b][1, 4] Oxazepine

-3,1'-naphthalene]-7-sulfonamide (6.11 g, 6.73 mmol) (crude product from step 7, 70% purity) in DCM (80 mL) was added NaBH(OAc) ₃ ( 7.14 g, 33.67 mmol). The mixture was stirred at 25°C for 16 hours. LCMS showed the reaction went well. To the reaction was added saturated aqueous NaHCO ₃ (80 mL), extracted with DCM (100 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA and PE to afford (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4, 5-Dihydro-2H-1,5-benzoxazepine

-3,1'-tetralin]-7-sulfonamide (2.30 g, 53% yield). LCMS calculated for _{C34H36ClN2O5S} (M+H) ⁺ : _m /z _{= 619.2} ; found: 619.3. ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.81-7.83(m,1H),7.24-7.28(m,2H),7.17-7.18(m,1H),6.95-7.06(m,6H), 6.78-6.80(m,4H),6.20(s,1H),4.15(m,4H),4.08-4.14(m,2H),3.68(s,6H),3.30-3.36(m,1H),3.23- 3.27 (m, 1H), 2.71-2.75 (m, 2H), 1.76-1.86 (m, 3H), 1.56-1.61 (m, 1H).

Intermediate 3

-3,1'-四氢化萘]-7-磺酰胺(3S)-6'-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1 ,5-Benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

-3,1'-四氢化萘]-5-基]甲基]环丁基]甲酯Step 1: [(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6'-chloro-spiro[2, 4-Dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-5-yl]methyl]cyclobutyl]methyl ester

-3,1'-四氢化萘]-7-磺酰胺(28.5g，46.03mmol)和乙酸[(1R,2R)-2-甲酰基环丁基]甲酯(8.63g，55.24mmol)于200mL DCM中的溶液。将所得混合物在室温下搅拌过夜。通过LC-MS监测反应。将另外2当量的硼氢化钠(3.48g，92.06mmol)和2,2,2-三氟乙酸(7.04mL，92.06mmol)加入到混合物中，接着搅拌3小时。通过加入甲醇(30mL)淬灭反应，接着缓慢加入饱和NaHCO₃溶液(300mL)。所得混合物用DCM(300mL×3)萃取。合并的有机层经Na₂SO₄干燥，过滤并减压浓缩。将残余物通过使用EtOAc/庚烷(5-40％)的硅胶柱快速色谱法纯化，得到呈白色固体的所需产物乙酸[(1R,2R)-2-[[(3S)-7-[双[(4-甲氧基苯基)甲基]氨磺酰基]-6'-氯-螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-5-基]甲基]环丁基]甲酯(34.5g，45.4mmol，98％产率)。关于C₄₀H₄₃ClN₂O₆S的LC-MS计算值[M+H]⁺：m/z＝759.28/760.28；实验值759.67/760.64。2,2,2-Trifluoroacetic acid (7.0 mL, 92 mmol) was added dropwise to a stirred solution of sodium borohydride (3.48 g, 92.0 mmol) in DCM (200 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes. Then (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzo Oxazepine

-3,1'-tetralin]-7-sulfonamide (28.5g, 46.03mmol) and [(1R,2R)-2-formylcyclobutyl]methyl acetate (8.63g, 55.24mmol) in 200mL solution in DCM. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS. Another 2 equivalents of sodium borohydride (3.48 g, 92.06 mmol) and 2,2,2-trifluoroacetic acid (7.04 mL, 92.06 mmol) were added to the mixture, followed by stirring for 3 hours. The reaction was quenched by the addition of methanol (30 mL), followed by the slow addition of saturated NaHCO ₃ solution (300 mL). The resulting mixture was extracted with DCM (300 mL x 3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by column flash chromatography on silica gel with EtOAc/heptane (5-40%) to give the desired product acetic acid [(1R,2R)-2-[[(3S)-7-[ Bis[(4-methoxyphenyl)methyl]sulfamoyl]-6'-chloro-spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-5-yl]methyl]cyclobutyl]methyl ester (34.5 g, 45.4 mmol, 98% yield). LC-MS calculated for _{C40H43ClN2O6S} [M+ _H ] ⁺ : m/z ₌ 759.28 _/ 760.28; found 759.67/760.64.

-3,1'-四氢化萘]-7-磺酰胺Step 2: (3S)-6'-Chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutane base]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

-3,1'-四氢化萘]-5-基]甲基]环丁基]甲酯(54.0g，71.1mmol)于THF(500mL)、甲醇(500mL)和水(500mL)中的溶液中加入单水合氢氧化锂(14.9g，355mmol)。将混合物在室温下搅拌过夜。除去溶剂，并用DCM(100mL×3)萃取水层。合并的有机层经Na₂SO₄干燥，过滤并减压浓缩，得到呈白色固体的(3S)-6'-氯-N,N-双[(4-甲氧基苯基)甲基]-5-[[(1R,2R)-2-(羟甲基)环丁基]甲基]螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-7-磺酰胺(52g，101％产率)，其不经进一步纯化即直接用于下一步骤。关于C₄₀H₄₅ClN₂O₆S的LC-MS计算值[M+H]⁺:m/z＝717.27/718.27；实验值717.6/718.6。To acetic acid [(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6'-chloro-spiro[2,4- Dihydro-1,5-benzoxazepine

A solution of -3,1'-tetralin]-5-yl]methyl]cyclobutyl]methyl ester (54.0 g, 71.1 mmol) in THF (500 mL), methanol (500 mL) and water (500 mL) Lithium hydroxide monohydrate (14.9 g, 355 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was removed, and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to give (3S)-6' _- chloro-N,N-bis[(4-methoxyphenyl)methyl]- 5-[[(1R,2R)-2-(Hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-tetralin]-7-sulfonamide (52 g, 101% yield), which was used directly in the next step without further purification. LC-MS calculated for _{C40H45ClN2O6S} [M+H] ⁺ : m _/ z ₌ 717.27 _/ 718.27; found 717.6/718.6.

-3,1'-四氢化萘]-7-磺酰胺Step 3: (3S)-6'-Chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methanol base]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

-3,1'-四氢化萘]-7-磺酰胺(52.0g，72.4mmol)于DCM(50mL)中的溶液。将所得混合物在-78℃搅拌40分钟。然后加入三乙胺(101mL，724mmol)。将溶液在-78℃再搅拌10分钟，并使其缓慢升温至0℃。在起始材料耗尽后，加入水(150mL)。分离有机层。用DCM(300mL×3)萃取水层。合并的有机层经硫酸钠干燥并浓缩。将残余物通过利用EtOAc/庚烷(5-50％)的硅胶柱快速色谱法纯化，得到呈白色固体的(3S)-6'-氯-N,N-双[(4-甲氧基苯基)甲基]-5-[[(1R,2R)-2-甲酰基环丁基]甲基]螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-7-磺酰胺(43g，83％产率)。关于C₄₀H₄₃ClN₂O₆S的LC-MS计算值[M+H]⁺:m/z＝715.25/716.26；实验值715.7/716.7。DMSO (20.5 mL, 289 mmol) was slowly added to a cooled (-78 °C) solution of oxalyl chloride (12.4 mL, 144.9 mmol) in DCM (1000 mL). Gas was generated during this addition. The mixture was stirred at -78°C for 30 minutes. Then (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl) was added over 5 minutes Cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

- A solution of 3,1'-tetralin]-7-sulfonamide (52.0 g, 72.4 mmol) in DCM (50 mL). The resulting mixture was stirred at -78°C for 40 minutes. Triethylamine (101 mL, 724 mmol) was then added. The solution was stirred at -78°C for an additional 10 minutes and allowed to warm slowly to 0°C. After the starting material was consumed, water (150 mL) was added. Separate the organic layer. The aqueous layer was extracted with DCM (300 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column flash chromatography on silica gel with EtOAc/heptane (5-50%) to afford (3S)-6'-chloro-N,N-bis[(4-methoxybenzene) as a white solid Base)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-tetralin]-7-sulfonamide (43 g, 83% yield). LC-MS calculated for _{C40H43ClN2O6S} [M+H] ⁺ : m _/ z ₌ 715.25 _/ 716.26; found 715.7/716.7.

-3,1'-四氢化萘]-7-磺酰胺和(3S)-6'-氯-N,N-双[(4-甲氧基苯基)甲基]-5-[[(1R,2R)-2-[(1R)-1-羟基烯丙基]环丁基]甲基]螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-7-磺酰胺Step 4: (3S)-6'-Chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1- Hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-tetralin]-7-sulfonamide and (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R ,2R)-2-[(1R)-1-Hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide

-3,1'-四氢化萘]-7-磺酰胺(43.0g，60.1mmol)。通过LC-MS监测反应。在起始材料耗尽后，然后在0℃下通过加入饱和NH₄Cl水溶液(300mL)淬灭反应。然后分离有机层，并且水层用乙酸乙酯(300mL×2)萃取。合并的有机层经Na₂SO₄干燥，过滤并减压浓缩。将残余物通过使用EtOAc/庚烷(5-40％)的硅胶柱快速色谱法纯化，得到两种产物：P1(较早洗脱产物：24.3g，40％)和P2(较迟洗脱产物：20g，33％)。Vinylmagnesium bromide (1.0 M in THF, 300 mL, 300 mmol) was diluted with THF (200 mL) in a 3-necked round bottom flask under nitrogen. (3S)-6'-Chloro-N,N-bis[(4-methoxyphenyl)methyl]-5 dissolved in THF (400 mL) was introduced dropwise through a dropping funnel at room temperature over 2 hours -[[(1R,2R)-2-Formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-tetralin]-7-sulfonamide (43.0 g, 60.1 mmol). The reaction was monitored by LC-MS. After the starting material was consumed, the reaction was then quenched at 0 °C by the addition of saturated aqueous _NH4Cl (300 mL). Then the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (300 mL×2). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by column flash chromatography on silica gel with EtOAc/heptane (5-40%) to give two products: P1 (early eluting product: 24.3 g, 40%) and P2 (late eluting product : 20g, 33%).

-3,1'-四氢化萘]-7-磺酰胺(Rt＝4.43分钟，根据LC-MS)。关于C₄₂H₄₈ClN₂O₆S的LC-MS计算值[M+H]⁺：m/z＝743.28/744.29；实验值743.76/744.78。¹H NMR(300MHz,CDCl₃)δ7.76(t,J＝7.2Hz,1H),7.53(d,J＝1.9Hz,1H),7.24–7.14(m,2H),7.12(d,J＝2.0Hz,1H),7.03–6.97(m,5H),6.79(t,J＝5.7Hz,4H),5.84–5.69(m,1H),5.16(d,J＝17.2Hz,1H),5.05(d,J＝10.4Hz,1H),4.26(t,J＝5.6Hz,4H),4.13(s,2H),3.97(d,J＝4.4Hz,1H),3.80(d,J＝1.8Hz,6H),3.74(d,J＝6.2Hz,1H),3.26(d,J＝14.2Hz,1H),3.09(dd,J＝15.0,9.3Hz,1H),2.93(d,J＝4.2Hz,1H),2.83–2.75(m,2H),2.48–2.35(m,1H),2.10–1.92(m,4H),1.82(m,3H),1.50(m,2H)。P1 is assigned as (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1 -Hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide (Rt = 4.43 min according to LC-MS). LC-MS calculated for _{C42H48ClN2O6S} [M+H] ⁺ : m/z ₌ 743.28 _/ 744.29; found 743.76 _/ 744.78. ¹ H NMR (300MHz, CDCl ₃ ) δ7.76(t, J=7.2Hz, 1H), 7.53(d, J=1.9Hz, 1H), 7.24–7.14(m, 2H), 7.12(d, J= 2.0Hz, 1H), 7.03–6.97(m, 5H), 6.79(t, J＝5.7Hz, 4H), 5.84–5.69(m, 1H), 5.16(d, J＝17.2Hz, 1H), 5.05( d,J=10.4Hz,1H),4.26(t,J=5.6Hz,4H),4.13(s,2H),3.97(d,J=4.4Hz,1H),3.80(d,J=1.8Hz, 6H), 3.74(d, J=6.2Hz, 1H), 3.26(d, J=14.2Hz, 1H), 3.09(dd, J=15.0, 9.3Hz, 1H), 2.93(d, J=4.2Hz, 1H), 2.83–2.75(m,2H), 2.48–2.35(m,1H), 2.10–1.92(m,4H), 1.82(m,3H), 1.50(m,2H).

-3,1'-四氢化萘]-7-磺酰胺(Rt＝4.13分钟，根据LC-MS)。关于C₄₂H₄₈ClN₂O₆S的LC-MS计算值[M+H]⁺：m/z＝743.28/745.29；实验值743.8/745.8。¹H NMR(300MHz,CDCl₃)δ7.75–7.68(m,1H),7.24–7.14(m,3H),7.12(d,J＝2.0Hz,1H),7.01(t,J＝8.3Hz,5H),6.79(d,J＝8.7Hz,4H),5.85(ddd,J＝17.0,10.4,6.4Hz,1H),5.29(dd,J＝17.2,1.2Hz,1H),5.17–5.08(m,1H),4.26(d,J＝8.4Hz,4H),4.14(d,J＝8.0Hz,3H),3.81(s,6H),3.69(d,J＝14.3Hz,1H),3.59(d,J＝12.9Hz,1H),3.31(d,J＝14.3Hz,1H),3.15(dd,J＝14.9,9.0Hz,1H),2.84–2.76(m,2H),2.67–2.56(m,1H),2.23–2.09(m,2H),2.03(m,2H),1.86–1.73(m,3H),1.59–1.46(m,2H)。and P2 is assigned as (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)- 1-Hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide (Rt = 4.13 min according to LC-MS). LC-MS calculated for _{C42H48ClN2O6S} [M+H] ⁺ : m _/ z ₌ 743.28 _/ 745.29; found 743.8/745.8. ¹ H NMR (300MHz, CDCl ₃ ) δ7.75–7.68(m,1H),7.24–7.14(m,3H),7.12(d,J=2.0Hz,1H),7.01(t,J=8.3Hz, 5H), 6.79(d, J=8.7Hz, 4H), 5.85(ddd, J=17.0, 10.4, 6.4Hz, 1H), 5.29(dd, J=17.2, 1.2Hz, 1H), 5.17–5.08(m ,1H),4.26(d,J=8.4Hz,4H),4.14(d,J=8.0Hz,3H),3.81(s,6H),3.69(d,J=14.3Hz,1H),3.59(d ,J=12.9Hz,1H),3.31(d,J=14.3Hz,1H),3.15(dd,J=14.9,9.0Hz,1H),2.84–2.76(m,2H),2.67–2.56(m, 1H), 2.23–2.09(m,2H), 2.03(m,2H), 1.86–1.73(m,3H), 1.59–1.46(m,2H).

-3,1'-四氢化萘]-7-磺酰胺(中间体3)Step 5: (3S)-6'-Chloro-5-[[(1R,2R)-2-[(1S)-1-Hydroxyallyl]cyclobutyl]methyl]spiro[2,4-di Hydrogen-1,5-benzoxazepine

-3,1'-Tetralin]-7-sulfonamide (Intermediate 3)

-3,1'-四氢化萘]-7-磺酰胺(24.3g，32.6mmol，P1，步骤4)和苯甲醚(23.7mL，218mmol)于DCM(240mL)中的溶液中加入2,2,2-三氟乙酸(243mL)。将混合物搅拌过夜。通过LC-MS监测反应。减压除去溶剂。用DCM(200mL)稀释残余物。混合物用饱和NaHCO₃水溶液(200mL×3)和盐水洗涤，经Na₂SO₄干燥，过滤并减压浓缩。将残余物通过利用EA/庚烷(5％-70％)的硅胶柱快速色谱法纯化，得到呈浅白色固体的(3S)-6'-氯-5-[[(1R,2R)-2-[(1S)-1-羟基烯丙基]环丁基]甲基]螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-7-磺酰胺(15.7g，31.2mmol，95％产率)。关于C₂₆H₃₂ClN₂O₄S的LC-MS计算值[M+H]⁺：m/z＝503.17/505.17；实验值503.5/505.5；¹H NMR(300MHz,CDCl₃)δ7.74(d,J＝8.5Hz,1H),7.55(d,J＝1.8Hz,1H),7.21(dd,J＝11.4,4.2Hz,2H),7.12–7.08(m,2H),6.97–6.94(m,1H),6.85(d,J＝8.6Hz,1H),5.90–5.76(m,1H),5.25(d,J＝17.2Hz,1H),5.16–5.08(m,1H),4.11(s,2H),3.88(d,J＝5.1Hz,1H),3.81(s,2H),3.27(d,J＝14.3Hz,1H),3.14(m,1H),2.84–2.75(m,2H),2.51(dd,J＝16.9,8.5 Hz,1H),2.08(m,3H),1.90(dd,J＝15.8,5.6 Hz,2H),1.63(m,3H),1.45(t,J＝12.1 Hz,1H)。To (3S)-6'-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxylene Propyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

2,2 , 2-Trifluoroacetic acid (243 mL). The mixture was stirred overnight. The reaction was monitored by LC-MS. The solvent was removed under reduced pressure. The residue was diluted with DCM (200 mL). The mixture was washed with saturated aqueous NaHCO ₃ (200 mL×3) and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column flash chromatography on silica gel with EA/heptane (5%-70%) to afford (3S)-6'-chloro-5-[[(1R,2R)-2 as an off-white solid -[(1S)-1-Hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-tetralin]-7-sulfonamide (15.7 g, 31.2 mmol, 95% yield). LC-MS calculated for C ₂₆ H ₃₂ ClN ₂ O ₄ S [M+H] ⁺ : m/z = 503.17/505.17; found 503.5/505.5; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.74 ( d,J=8.5Hz,1H),7.55(d,J=1.8Hz,1H),7.21(dd,J=11.4,4.2Hz,2H),7.12–7.08(m,2H),6.97–6.94(m ,1H),6.85(d,J=8.6Hz,1H),5.90–5.76(m,1H),5.25(d,J=17.2Hz,1H),5.16–5.08(m,1H),4.11(s, 2H), 3.88(d, J=5.1Hz, 1H), 3.81(s, 2H), 3.27(d, J=14.3Hz, 1H), 3.14(m, 1H), 2.84–2.75(m, 2H), 2.51(dd, J=16.9, 8.5 Hz, 1H), 2.08(m, 3H), 1.90(dd, J=15.8, 5.6 Hz, 2H), 1.63(m, 3H), 1.45(t, J=12.1 Hz ,1H).

2-allyloxy-2-methylpropionic acid

This compound can be prepared by treating ethyl 2-hydroxy-2-methyl-propionate with NaH in THF, followed by reaction with allyl bromide. The resulting product is then reacted with sodium hydroxide to give 2-allyloxy-2-methyl-propionic acid.

Example 32

(3R,6R,7S,8E,22S)-6'-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-sulfur Hetero-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraen-22,1'-tetrahydronaphthalene]-13-one

-3,1'-四氢化萘]-5-基]甲基]环丁基]烯丙基]酯Step 1: 2-allyloxy-2-methyl-propanoic acid [(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy- 2-Methyl-propionyl)sulfamoyl]-6'-chloro-spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-5-yl]methyl]cyclobutyl]allyl]ester

-3,1'-四氢化萘]-7-磺酰胺(200.0 mg，0.40mmol，中间体3)、2-烯丙氧基-2-甲基-丙酸(171.96 mg，1.19 mmol)、EDCI(0.47mL，2.39mmol)和DMAP(291.43mg，2.39mmol)于DCM(4mL)中的溶液在室温下搅拌16小时。LC-MS表明反应完成。将反应用DCM稀释并用0.5N HCl洗涤。有机相经Na₂SO₄干燥并减压浓缩。将残余物通过利用EtOAc/庚烷(10％至20％)的硅胶柱(12g)快速色谱法纯化，得到2-烯丙氧基-2-甲基-丙酸[(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-烯丙氧基-2-甲基-丙酰基)氨磺酰基]-6'-氯-螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-5-基]甲基]环丁基]烯丙基]酯(300mg，99.9％产率)。关于C₄₀H₅₂ClN₂O₈S的LC-MS计算值[M+H]⁺：m/z＝755.31/757.31；实验值：755.1/757.4。(3S)-6'-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro- 1,5-Benzoxazepine

-3,1'-tetralin]-7-sulfonamide (200.0 mg, 0.40 mmol, intermediate 3), 2-allyloxy-2-methyl-propionic acid (171.96 mg, 1.19 mmol), EDCI (0.47 mL, 2.39 mmol) and DMAP (291.43 mg, 2.39 mmol) in DCM (4 mL) was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction was diluted with DCM and washed with 0.5N HCl. The organic phase was dried over _Na2SO4 and concentrated _under reduced pressure. The residue was purified by flash chromatography on a silica gel column (12 g) with EtOAc/heptane (10% to 20%) to give 2-allyloxy-2-methyl-propanoic acid [(1S)-1-[ (1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propionyl)sulfamoyl]-6'-chloro-spiro[2,4-di Hydrogen-1,5-benzoxazepine

-3,1'-tetrahydronaphthalene]-5-yl]methyl]cyclobutyl]allyl]ester (300 mg, 99.9% yield). LC-MS calculated for _{C40H52ClN2O8S} [M+H] ⁺ : m/z ₌ 755.31 _/ 757.31; found: _755.1 /757.4.

-3,1'-四氢化萘]-7-基]磺酰基-丙酰胺Step 2: 2-Allyloxy-2-methyl-N-[(3S)-6'-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl ]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-Tetralin]-7-yl]sulfonyl-propionamide

-3,1'-四氢化萘]-5-基]甲基]环丁基]烯丙基]酯(300mg，0.40mmol)和单水合氢氧化锂(83.3mg，1.99mmol)于THF/MeOH/H₂O(各0.3mL)中的溶液在45℃加热4小时。LC-MS表明反应完成。将反应用1N HCl调节至pH3-4并用DCM萃取。将合并的有机层用饱和NaHCO₃水溶液和盐水洗涤，经Na₂SO₄干燥，过滤并减压浓缩，得到2-烯丙氧基-2-甲基-N-[(3S)-6'-氯-5-[[(1R,2R)-2-[(1S)-1-羟基烯丙基]环丁基]甲基]螺[2,4-二氢-1,5-苯并氧氮杂

-3,1'-四氢化萘]-7-基]磺酰基-丙酰胺(175mg，70％产率)，其未经进一步纯化即使用。LCMS：关于C₃₃H₄₂ClN₂O₆S的计算值[M+H]⁺：m/z＝629.24/631.24；实验值：628.9/631.2。2-allyloxy-2-methyl-propionic acid [(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2- Methyl-propionyl)sulfamoyl]-6'-chloro-spiro[2,4-dihydro-1,5-benzoxazepine

-3,1'-tetrahydronaphthalene]-5-yl]methyl]cyclobutyl]allyl]ester (300mg, 0.40mmol) and lithium hydroxide monohydrate (83.3mg, 1.99mmol) in THF/MeOH The solution in _H2O (0.3 mL each) was heated at 45 °C for 4 h. LC-MS indicated the reaction was complete. The reaction was adjusted to pH 3-4 with 1N HCl and extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-allyloxy-2-methyl-N-[(3S)-6′- Chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine miscellaneous

-3,1'-Tetralin]-7-yl]sulfonyl-propionamide (175 mg, 70% yield) which was used without further purification. LCMS: _Calcd . for _{C33H42ClN2O6S} [M+H] ⁺ : m/z ₌ 629.24/631.24; found: 628.9/ _631.2 .

Step 3: (3R,6R,7S,8E,22S)-6'-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa- 15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1'-tetrahydronaphthalene]-13 -ketone

-3,1'-四氢化萘]-7-基]磺酰基-2-甲基-丙酰胺(1.40g，2.23mmol)于DCE(1230mL)中的溶液用N₂鼓泡10分钟。加入1,3-双(2,4,6-三甲基苯基)-4,5-二氢咪唑-2-亚基[2-(异丙氧基)-5-(N,N-二甲基氨基磺酰基)苯基]亚甲基钌(II)二氯化物(Zhan Catalyst 1B)(326mg，0.45mmol)，并且将所得浅绿色溶液进一步用N₂鼓泡5分钟，并在N₂下在40℃加热2小时。将反应在减压下浓缩，并且残余物通过利用EtOAc/庚烷(10％至70％)的硅胶柱快速柱色谱法纯化，得到两种产物：P1(较早洗脱产物，160mg，11％产率)和P2(较迟洗脱产物，647mg，47％产率)。2-allyloxy-N-[(3S)-6'-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl ]spiro[2,4-dihydro-1,5-benzoxazepine

A solution of -3,1'-tetralin]-7-yl]sulfonyl-2-methyl-propionamide (1.40 g, 2.23 mmol) in DCE (1230 mL) was bubbled with _N2 for 10 min. Add 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(isopropoxy)-5-(N,N-di Methylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (Zhan Catalyst 1B) (326mg, 0.45mmol), and the resulting light green solution was further bubbled with _N2 for 5 minutes, and heated under _N2 heated at 40°C for 2 hours. The reaction was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel with EtOAc/heptane (10% to 70%) to afford two products: P1 (the earlier eluting product, 160 mg, 11% yield) and P2 (late eluting product, 647 mg, 47% yield).

)；流速＝1mL/min；流动相：90％ MeCN/H₂O(含0.1％ HCO₂H)10分钟λ＝220nm。tR＝3.2分钟。关于C₃₁H₃₈ClN₂O₆S的LC-MS计算值[M+H]⁺：m/z＝601.21/603.21；实验值601.6/603.6；¹H NMR(300MHz,CDCl₃)δ9.15(s,1H),7.69(d,J＝8.5Hz,1H),7.53(dd,J＝8.3,2.1Hz,1H),7.20(dd,J＝8.6,2.2Hz,1H),7.12(s,1H),7.06(d,J＝1.8Hz,1H),7.02(d,J＝8.3Hz,1H),5.84–5.72(m,2H),4.24(d,J＝3.3Hz,1H),4.13(t,J＝7.2Hz,2H),4.00(dd,J＝13.2,4.5Hz,1H),3.88(d,J＝12.5Hz,1H),3.72(d,J＝14.6Hz,1H),3.40–3.24(m,3H),2.84–2.71(m,3H),2.43–2.33(m,1H),2.01(d,J＝15.5Hz,2H),1.94–1.81(m,4H),1.75–1.58(m,2H),1.54(d,J＝14.5Hz,1H),1.45(s,3H),1.41(s,3H)。P2 was assigned as (3R,6R,7S,8E,22S)-6'-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa -15-Thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1'-tetrahydronaphthalene]- 13-Kone (Example 32). HPLC: main product, C18 column (4.6 * 150mm,

); flow rate = 1 mL/min; mobile phase: 90% MeCN/H ₂ O (containing 0.1% HCO ₂ H) for 10 minutes λ = 220 nm. tR = 3.2 minutes. LC-MS calculated for C ₃₁ H ₃₈ ClN ₂ O ₆ S [M+H] ⁺ : m/z=601.21/603.21; found 601.6/603.6; ¹ H NMR (300MHz, CDCl ₃ ) δ9.15( s,1H),7.69(d,J=8.5Hz,1H),7.53(dd,J=8.3,2.1Hz,1H),7.20(dd,J=8.6,2.2Hz,1H),7.12(s,1H ), 7.06(d, J=1.8Hz, 1H), 7.02(d, J=8.3Hz, 1H), 5.84–5.72(m, 2H), 4.24(d, J=3.3Hz, 1H), 4.13(t ,J=7.2Hz,2H),4.00(dd,J=13.2,4.5Hz,1H),3.88(d,J=12.5Hz,1H),3.72(d,J=14.6Hz,1H),3.40–3.24 (m,3H),2.84–2.71(m,3H),2.43–2.33(m,1H),2.01(d,J＝15.5Hz,2H),1.94–1.81(m,4H),1.75–1.58(m , 2H), 1.54 (d, J=14.5Hz, 1H), 1.45 (s, 3H), 1.41 (s, 3H).

)；流速＝1mL/min；流动相：90％ MeCN/H₂O(含0.1％ HCO₂H)10分钟λ＝220nm。tR＝4.3分钟。关于C₃₁H₃₈ClN₂O₆S的LC-MS计算值[M+H]⁺：m/z＝601.21/603.21；实验值601.6/603.6；¹H NMR(300MHz,CDCl₃)δ9.22(s,1H),7.68(t,J＝8.3Hz,1H),7.55(dd,J＝8.4,2.1Hz,1H),7.20(dd,J＝8.5,2.1Hz,1H),7.13(dd,J＝9.6,2.0Hz,2H),7.03(d,J＝8.4Hz,1H),5.92–5.75(m,2H),4.22–4.14(m,1H),4.00(dd,J＝13.4,4.9Hz,1H),3.89(dd,J＝13.3,2.9Hz,1H),3.81–3.61(m,4H),3.33(d,J＝14.5Hz,1H),3.15(dd,J＝15.1,9.2Hz,1H),2.79(d,J＝9.2Hz,2H),2.53(d,J＝5.2Hz,1H),2.33–2.22(m,1H),2.08–1.92(m,4H),1.81(dd,J＝35.4,6.4Hz,2H),1.71–1.57(m,2H),1.45(s,3H),1.42(s,3H)。and P1 is designated as (3R,6R,7S,8Z,22S)-6'-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxo Hetero-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1'-tetrahydronaphthalene] -13-ones (Example 33). P1: Minor product, C18 column (4.6×150mm,

); flow rate = 1 mL/min; mobile phase: 90% MeCN/H ₂ O (containing 0.1% HCO ₂ H) for 10 minutes λ = 220 nm. tR = 4.3 minutes. LC-MS calculated for C ₃₁ H ₃₈ ClN ₂ O ₆ S [M+H] ⁺ : m/z=601.21/603.21; found 601.6/603.6; ¹ H NMR (300MHz, CDCl ₃ ) δ9.22( s,1H),7.68(t,J=8.3Hz,1H),7.55(dd,J=8.4,2.1Hz,1H),7.20(dd,J=8.5,2.1Hz,1H),7.13(dd,J =9.6,2.0Hz,2H),7.03(d,J=8.4Hz,1H),5.92–5.75(m,2H),4.22–4.14(m,1H),4.00(dd,J=13.4,4.9Hz, 1H), 3.89(dd, J=13.3, 2.9Hz, 1H), 3.81–3.61(m, 4H), 3.33(d, J=14.5Hz, 1H), 3.15(dd, J=15.1, 9.2Hz, 1H ),2.79(d,J=9.2Hz,2H),2.53(d,J=5.2Hz,1H),2.33–2.22(m,1H),2.08–1.92(m,4H),1.81(dd,J= 35.4, 6.4Hz, 2H), 1.71–1.57(m, 2H), 1.45(s, 3H), 1.42(s, 3H).

Formula (I)

N,N-Dimethylcarbamate[(3R,6R,7S,8E,22S)-6'-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20 -Dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1'-tetra Hydrogenated naphthalene]-7-yl] ester

(3R,6R,7S,8E,22S)-6'-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa -15-Thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1'-tetrahydronaphthalene]- To a solution of 13-ketone (13.0 mg, 0.02 mmol, Example 32) in THF (0.5 mL) was added sodium hydride (4.3 mg, 0.11 mmol). After 10 minutes, N,N-dimethylcarbamoyl chloride (4.6 mg, 0.04 mmol) was added followed by DMAP (5.3 mg, 0.04 mmol). The mixture was stirred at room temperature for 6 hours, diluted with DCM and acidified to pH 5-6 with 0.5N HCl. The organic phase was separated, washed with water and brine, dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by preparative HPLC on a C18 column (30×250 mm, 10 μm) with 20% to 100% ACN/H ₂ O to afford N,N-dimethylcarbamate [(3R,6R ,7S,8E,22S)-6'-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14- Diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraen-22,1'-tetralin]-7-yl]ester (6mg, 38% Yield). LCMS calculated for _{C34H43ClN3O7S} [M+H] ⁺ : m _/ z ₌ 672.25 _/ 674.25; found: 672.45/674.37. ¹ H NMR (600MHz, CDCl ₃ ) δ9.08 (br s, 1H), 7.67 (d, J = 8.5Hz, 1H), 7.49 (dd, J = 8.3, 2.2Hz, 1H), 7.17 (dd, J ＝8.5,2.4Hz,1H),7.08(d,J＝2.2Hz,1H),7.04–6.95(m,2H),5.86–5.78(m,1H),5.74–5.67(m,1H),5.30( t, J＝4.5Hz, 1H), 4.15(d, J＝12.2Hz, 1H), 4.12–4.05(m, 2H), 3.76–3.72(m, 1H), 3.70(d, J＝14.8Hz, 1H ),3.43(dd,J=15.1,4.7Hz,1H),3.37(d,J=14.7Hz,1H),3.21(dd,J=15.1,9.3Hz,1H),2.95(d,J=14.6Hz ,6H),2.83–2.73(m,3H),2.37(dtd,J＝15.2,10.2,9.7,5.5Hz,1H),2.06–1.90(m,3H),1.88–1.77(m,3H),1.67 –1.60(m,2H),1.56(s,2H),1.43(s,6H).

Preparation of Crystal Forms

Formula I – Form I – Method 1

Formula I (24.37 mg (0.036 mmol); amorphous) was added to a 4 mL vial. Methanol (1.0 mL) was added to give a nearly clear solution. The mixture was stirred overnight at 50 °C to obtain a slurry. The slurry was cooled to room temperature and stirred for 4 hours. The mixture was filtered and the filter cake was dried under vacuum at 40-45°C overnight to afford 18.1 mg (74.27%) of Formula I-Form I.

XRPD: Figure 1.

DSC: Figure 2.

TGA: Figure 3.

DVS: Figure 4A and Figure 4B.

XRPD before and after DVS: Fig. 5.

Formula I – Form I – Method 2

Formula I (23.7 mg (0.036 mmol) amorphous) was added to a 4 mL vial. Methanol (0.4 mL) and water (0.1 mL) were added to give a thin slurry. The mixture was stirred at 50 °C for 3 hours to form a slurry. The mixture was cooled to room temperature and stirred for 20 minutes. The mixture was filtered to give Formula I-Form I.

Formula I – Form II – Method 1

Formula I (400 mg; amorphous) was added to a 20 mL vial. Ethanol (7.0 mL) was added to obtain a slurry. The mixture was stirred at 70°C for 20 minutes to obtain a solution. The solution was cooled slowly to obtain a slurry. The slurry was allowed to stand over a weekend and then filtered to give Formula I-Form II.

XRPD: Figure 6.

DSC: Figure 7.

The solid was dried under vacuum at 45-46° C. overnight to afford Formula I as amorphous.

Formula I Choline Salt (Formula IA)

Formula I (168.0 mg (0.25 mmol, 1.0 equiv) amorphous) was added to a 25 mL vial. Ethyl acetate (4.0 mL) was added to give a clear solution. 275 μL of 1.0 M choline hydroxide in IPA (0.275 mmol, 1.1 equiv) was added. The mixture was stirred for 5 minutes to obtain a clear solution. The mixture was stirred continuously overnight to obtain a slurry. The mixture was filtered and the filter cake was vacuum dried overnight at room temperature to yield 150.2 mg (77.4%) of the choline salt of formula I.

XRPD: Figure 8.

DSC: Figure 9.

TGA: Figure 10

NMR spectrum (600 MHz in CDCl ₃ ): FIG. 11 .

Formula I benzathine salt (formula IB)

Formula I (168.0 mg (0.25 mmol, 1.0 equiv) amorphous) was added to a 25 mL vial. Ethyl acetate (4.0 mL) was added to give a clear solution. 275 μL of 1.0 M benzathine in IPA (0.275 mmol, 1.1 equiv) was added. The mixture was stirred for 5 minutes to obtain a clear solution. The mixture was stirred continuously overnight to obtain a slurry. The mixture was filtered and the filter cake was vacuum dried overnight at room temperature to yield 100.2 mg (44.0%) of the benzathine salt of formula I.

XRPD: Figure 12.

DSC: Figure 13.

TGA: Figure 14

NMR spectrum (600 MHz in CDCl ₃ ): FIG. 15 .

Formula I imidazolium salt (formula IC)

Formula I (168.0 mg (0.25 mmol, 1.0 equiv) amorphous) was added to a 25 mL vial. Ethyl acetate (4.0 mL) was added to give a clear solution. 18.9 mg imidazole (0.275 mmol, 1.1 equiv) was added. The mixture was stirred for 5 minutes to obtain a clear solution. The mixture was stirred continuously overnight to obtain a slurry. The mixture was filtered and the filter cake was vacuum dried overnight at room temperature to yield 118.0 mg (63.8%) of the imidazolium salt of formula I.

XRPD: Figure 16.

DSC: Figure 17.

TGA: Figure 18

NMR spectrum (600 MHz in CDCl ₃ ): FIG. 19 .

Formula I piperazine salt - (Form 1)

Formula I (168.0 mg (0.25 mmol, 1.0 equiv) amorphous) was added to a 25 mL vial. Ethyl acetate (4.0 mL) was added to give a clear solution. 23.2 mg piperazine (0.275 mmol, 1.1 equiv) was added. The mixture was stirred for 5 minutes to obtain a clear solution. The mixture was stirred continuously overnight to obtain a slurry. The mixture was filtered and the filter cake was dried under vacuum at room temperature overnight to yield 100.5 mg (52.6%) of the piperazine salt of formula I.

XRPD: Figure 20.

DSC: Figure 21.

TGA: Figure 22.

NMR spectrum (600 MHz in CDCl ₃ ): FIG. 23 .

Formula I piperazine salt - (Form 2)

Formula I (25.0 mg; 0.037 mmol) was added to a 4 mL vial. 0.5 mL of acetonitrile was added and the mixture was stirred for 30 minutes. Piperazine (0.056 mmol, 1.50 equiv) was added and the mixture was stirred for 2 hours, then at 50 °C for 2 hours. The mixture is cooled, then stirred at room temperature overnight, then filtered to give the piperazine salt of formula I.

XRPD: Figure 20A.

DSC: Figure 21A.

Formula I piperazine salt - (Form 3)

Formula I (25.0 mg; 0.037 mmol) was added to a 4 mL vial. 0.5 mL of methanol was added and the mixture was stirred for 30 minutes. Piperazine (0.056 mmol, 1.50 equiv) was added and the mixture was stirred for 2 hours, then at 50 °C for 2 hours. The mixture is cooled, then stirred at room temperature overnight, then filtered to give the piperazine salt of formula I.

XRPD: Figure 20B.

Formula I piperazine salt

Formula I (25.0 mg; 0.037 mmol) was added to a 4 mL vial. 0.5 mL THF/methanol was added and the mixture was stirred for 30 minutes. Piperazine (0.056 mmol, 1.50 equiv) was added and the mixture was stirred for 2 hours, then at 50 °C for 2 hours. The mixture is cooled, then stirred at room temperature overnight, then filtered to give the piperazine salt of formula I.

Formula I piperidinium salt (form 1)

Formula I (168.0 mg (0.25 mmol, 1.0 equiv) amorphous) was added to a 25 mL vial. Ethyl acetate (4.0 mL) was added to give a clear solution. 23.4 mg 4.5 mg piperidine (0.275 mmol, 1.1 equiv) was added. The mixture was stirred for 5 minutes to obtain a clear solution. The mixture was stirred continuously overnight to obtain a slurry. The mixture was filtered and the filter cake was vacuum dried overnight at room temperature to yield 110.8 mg (64.2%) of the piperidine salt of formula I.

XRPD: Figure 24.

DSC: Figure 25.

TGA: Figure 26.

NMR spectrum (600 MHz in CDCl ₃ ): FIG. 27 .

Formula I-Piperidine Salt – Method 2

The piperidine salt of formula I was also prepared by reacting the free acid of formula I with 2.0 equivalents of piperidine in IPA/MeOH.

Formula I-Piperidine Salt – (Form 2)

The piperidine salt of formula I is also prepared by reaction of the free acid of formula I with piperidine in THF/MeOH.

XRPD: Figure 24A.

Formula I - Ethylenediamine Salt - (Form 1)

A mixture of the free acid of formula I (1.0 equiv) and ethylenediamine (2.0 equiv) was stirred in isopropanol/MeOH to give the ethylenediamine salt as a crystalline solid.

XRPD: Figure 32.

NMR spectrum: Figure 33.

Formula I - Ethylenediamine Salt - (Form 2)

A mixture of the free acid of formula I (1.0 equiv) and ethylenediamine (1.25 equiv) was stirred in THF/MeOH (1:5 mL) to give the ethylenediamine salt as a crystalline solid.

XRPD: Figure 32A.

Formula I 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt

Formula I (168.0 mg (0.25 mmol, 1.0 equiv) amorphous) was added to a 25 mL vial. Ethyl acetate (4.0 mL) was added to give a clear solution. 275 [mu]l of 1.0 M ethylenediamine in acetone (0.275 mmol, 1.1 equiv) was added. The mixture was stirred for 5 minutes to obtain a clear solution. The mixture was stirred continuously overnight to obtain a slurry. The mixture was filtered and the filter cake was vacuum dried overnight at room temperature to yield 102.2 mg (63.8%) of 4-((2-aminoethyl)amino)-4-methylpentan-2-one salt of formula I.

4-((2-Aminoethyl)amino)-4-methylpentan-2-one is believed to be formed in situ by the reaction of ethylenediamine with acetone.

XRPD: Figure 34.

DSC: Figure 35.

TGA: Figure 36.

NMR spectrum (600 MHz in CDCl ₃ ): FIG. 37 .

Formula I – Potassium salt

The potassium salt of formula I is prepared by reacting the free acid of formula I with potassium hydroxide (2M in water, 2.0 equivalents) in ethanol.

XRPD: Figure 28.

DSC: Figure 29.

The potassium salt of formula I was also prepared by reacting the free acid of formula I with potassium hydroxide (2M in water, 2.0 equivalents) in isopropanol.

Formula I – (S)-(-)-α-methylbenzylamine salt

Formula I - (S)-(-)-α-methylbenzylamine salts are prepared by reaction of formula I free acid with (S)-(-)-α-methylbenzylamine (1.5 equiv) in THF/methanol .

XRPD: Figure 30.

DSC: Figure 31.

Instrumental method

X-ray powder diffraction (XRPD)

XRPD patterns can be collected by a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced by an Optix long fine focus source. The elliptical graded multilayer mirror is used to focus Cu Kα X-rays through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the position of the observed Si 111 peak was consistent with the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. Beam stops, short anti-scatter extensions, and anti-scatter knife edges are used to minimize background from air. Soller slits for the incident and diffracted beams are used to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) at a distance of 240 mm from the sample and Data Collector software version 2.2b.

铜(Cu)。X射线功率：30KV，15mA。XRPD patterns can also be collected with a Rigaku MiniFlex X-ray powder diffractometer (XRPD) instrument. X-ray radiation comes from a K _b filter

Copper (Cu). X-ray power: 30KV, 15mA.

Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)

Thermal analysis can be performed using a Mettler Toledo TGA/DSC3+ analyzer. Temperature calibration using phenyl salicylate, indium, tin and zinc. The samples were placed in aluminum pans. The sample was sealed, the lid pierced, and inserted into the TG furnace. The furnace was heated under nitrogen.

DSC can also be acquired using TA Instruments Differential Scanning Calorimetry with an autosampler, model Q20, using a scan rate of 10°C/min and a nitrogen flow of 50 mL/min.

TGA can be collected using a TGA Q500 from TA Instruments using a scan rate of 20°C/min.

Dynamic Vapor Sorption (DVS)

Dynamic vapor sorption experiments can be performed using a VTI SGA-Cx100 Symmetrical Vapor Sorption Analyzer. The hygroscopicity curve was completed in three cycles, 10% RH increments, adsorption from 5% to 95% RH, followed by desorption from 95% to 5% RH in 10% increments. The equilibration standard is 0.0050 wt% within 5 minutes, and the maximum equilibration time is 180 minutes. All adsorption and desorption were performed at room temperature (23-25°C). No pre-drying step was performed on the samples.

biometrics

Cell-Free Mcl-1: Bim Affinity Assay (Mcl-1 Bim)

The binding affinity of each compound was measured via a fluorescence polarization competition assay, in which the compound competes with the ligand for the same binding site, resulting in a dose-dependent reduction in anisotropy. The tracer ligand used was a fluorescein isothiocyanate-labeled peptide (FITC-ARIAQELRRIGDEFNETYTR) derived from Bim (GenScript).

The assay was performed in black half-area 96-well NBS plates (Corning) containing 15 nM of MCL-1 (BPS Bioscience), 5 nM of FITC-Bim, and 3-fold serial dilutions of test compounds in a total volume of 50 μL of assay buffer ( 20 mM HEPES, 50 mM NaCl, 0.002% Tween 20, 1 mM TCEP and 1% DMSO). The reaction plate was incubated for 1 hour at room temperature. Changes in anisotropy were measured using an Envision multimode plate reader (PerkinElmer) at an emission wavelength of 535 nm. Fluorescence polarization was calculated in mP, and percent inhibition was calculated by % inhibition = 100 x (mP _DMSO - mP)/(mP _DMSO - mP _PC ), where mP _DMSO was the DMSO control and mP _PC was the positive control. _IC50 values were determined from 10-point dose-response curves by fitting the percent inhibition against compound concentration using GraphPad Prism software. The inhibition constant K _i was then calculated according to the Nikolovska-Coleska equation (Anal. Biochem., 2004, 332, 261 ),

where [I] ₅₀ is the concentration of free inhibitor at 50% inhibition, [L] ₅₀ is the concentration of free labeled ligand at 50% inhibition, [P] ₀ is the concentration of free protein at 0% inhibition, and _Kd is Dissociation constants for protein-ligand complexes. See Table A.

Caspase 3/7 activity assay

3/7检测缓冲液(G8093，Promega)，在室温下温育30-60分钟。使用384孔发光模式用酶标仪(PheraStar，BMG Labtech)读取板。Aliquots of 10 μL of prepared H929 cells (1:1 ratio of cells:trypan blue (#1450013, Bio-Rad)) were dispensed onto cell counting slides (#145-0011, Bio-Rad), And the cell density and cell viability were obtained using a cell counter (TC20, Bio-Rad). Remove an appropriate volume of resuspended cells from the culture flask to accommodate 2000 cells/well, 5 μL/well. For each FBS concentration (10%, 0.1%) to be assayed, H929 cells were transferred to 50 mL Erlenmeyer flasks (#430290, Corning). Centrifuge at 1000 rpm for 5 minutes using a table top centrifuge (SPINCHRON 15, Beckman). Discard the supernatant and resuspend the cell pellet in a solution containing sodium pyruvate (100mM) (#25-000-CL, Corning), HEPES buffer (1M) (#25-060-CL, Corning) and glucose (200g /L) (A24940-01, Gibco) and appropriate FBS (F2422-500ML, Sigma) concentrations in modified RPMI 1640 (#10-040-CV, Corning) cell culture medium to bring the cell density to 400,000 cells/mL . Dispense 5 μL of resuspended H929 in a 384-well low-volume TC-treated plate (#784080, Greiner Bio-one) using a standard cartridge (#50950372, Thermo Scientific) on a Multidrop Combi (#5840310, Thermo Scientific) in a laminar flow chamber cells/well. Compounds were dispensed onto the plate using a digital liquid dispenser (D300E, Tecan). Plates were incubated for 4 hours at 37°C in a humidified tissue culture incubator. Add 5 μL prepared

3/7 detection buffer (G8093, Promega), incubated at room temperature for 30-60 minutes. Plates were read with a microplate reader (PheraStar, BMG Labtech) using the 384-well luminescence mode.

Cell viability assay (H929 10FBS)

检测缓冲液(G7570，Promega)或ATPlite 1Step检测试剂(#6016731，Perkin Elmer)，在室温下温育30-60分钟。使用384孔发光模式用酶标仪(PheraStar，BMG Labtech)读取板。Aliquots of 10 μL of prepared H929 cells (1:1 ratio of cells:trypan blue (#1450013, Bio-Rad)) were dispensed onto cell counting slides (#145-0011, Bio-Rad), And the cell density and cell viability were obtained using a cell counter (TC20, Bio-Rad). Remove an appropriate volume of resuspended cells from the culture flask to accommodate 4000 cells/well, 10 μL/well. H929 cells were transferred to a 50 mL Erlenmeyer flask (#430290, Corning). Centrifuge at 1000 rpm for 5 minutes using a table top centrifuge (SPINCHRON 15, Beckman). Discard the supernatant and resuspend the cell pellet in a solution containing 10% FBS (F2422-500 ML, Sigma), sodium pyruvate (100 mM) (#25-000-CL, Corning), HEPES buffer (1M) (# 25-060-CL, Corning) and glucose (200 g/L) (A24940-01, Gibco) in Modified RPMI 1640 (#10-040-CV, Corning) cell culture medium to a cell density of 400,000 cells/mL . Dispense 10 μL of resuspended H929 in a 384-well low-volume TC-treated plate (#784080, Greiner Bio-one) using a standard cartridge (#50950372, Thermo Scientific) on a Multidrop Combi (#5840310, Thermo Scientific) in a laminar flow chamber cells/well. Compounds were dispensed onto the plate using a digital liquid dispenser (D300E, Tecan). Plates were incubated for 24 hours at 37°C in a humidified tissue culture incubator. Add 10 μL prepared

Detection buffer (G7570, Promega) or ATPlite 1 Step detection reagent (#6016731, Perkin Elmer), incubated at room temperature for 30-60 minutes. Plates were read with a microplate reader (PheraStar, BMG Labtech) using the 384-well luminescence mode.

Cytotoxicity Study in NCI-H929 Cells

Cytotoxicity studies were performed in the NCI-H929 multiple myeloma cell line. Cells were maintained in supplemented with 10% v/v FBS (GE Healthcare, catalog #: SH30910.03), 10 mM HEPES (Corning, catalog #: 25-060-CI), 1 mM sodium pyruvate (Corning Cellgro, catalog #: 25 -000-CI and 2500 mg/L glucose (Gibco, catalog #: A24940-01) in RPMI 1640 (Corning Cellgro, catalog #: 10-040-CV). Cells were seeded in 96 wells at a density of 75000 cells/well Plate. Compounds dissolved in DMSO were plated in duplicate using a digital dispenser (Tecan D300E) and tested in 9-point 3-fold serial dilutions. Cells were incubated in a 37°C _incubator with 5% CO for 24 h. Cell viability was measured using Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13) according to the manufacturer’s instructions. After addition of the reagents, the cells were incubated at 37°C with 5% CO _for 4 hours and treated with enzyme _OD values were measured with a plate reader (iMark microplate reader, Bio-Rad). The background from medium-only wells was averaged and subtracted from all readings. The _OD values were then normalized to the DMSO control The percentage of viable cells (relative to DMSO vehicle control) was obtained and plotted in Graphpad Prism ([Inhibitor] vs. normalized response - variable slope; equation: Y=100/(1+(X^Hill slope )/( _IC50 ^Hill slope))) to determine the _IC50 value (the concentration of compound that inhibits half the maximal activity).

Table A - Cell-free Mcl-1: Bim affinity assay (Mcl-1 Bim) and cell viability assay (H929_10FBS)

+++Ki < 1 nM; ++Ki = 1 nM - 100 nM; ### IC ₅₀ < 500 nM; ## IC ₅₀ < 1000 nM; #IC ₅₀ > 1000 nM; NT = not tested.

Claims (150)

1. A crystalline form of a compound of formula I:

2. the crystalline form of claim 1, wherein the crystalline form is formula I-form 1.

3. The crystalline form of claim 1 or claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in figure 1.

4. The crystalline form of any one of claims 1-3, characterized by an X-ray powder diffraction pattern comprising peaks at 11.2, 13.9, 17.1, 17.7, and 20.8 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

5. The crystalline form of any preceding claim, characterized by an X-ray powder diffraction pattern comprising peaks at 13.9, 17.1, 17.7, 20.8 and 21.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

6. The crystalline form of any one of the preceding claims, characterized by an X-ray powder diffraction pattern comprising peaks at 11.2, 13.9, 17.1, 17.7, 20.8, 21.9, and 25.0 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

7. The crystalline form of any preceding claim, characterized by an X-ray powder diffraction pattern comprising peaks at 9.4, 11.2, 13.9, 17.1, 17.7, 20.8, 21.9, 25.0 and 27.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

8. The crystalline form of any preceding claim, characterized by an X-ray powder diffraction pattern comprising peaks at 9.4, 11.2, 13.9, 17.1, 17.7, 20.8, 21.9, 25.0 and 27.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

9. The crystalline form of any preceding claim, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 2 when heated at a rate of 10 ℃/min.

10. The crystalline form of any preceding claim, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 81 ℃ when heated at a rate of 10 ℃/min.

11. The crystalline form of any one of the preceding claims, characterized by a thermogravimetric analysis curve substantially as shown in figure 3 when heated at a rate of 20 ℃/min.

12. The crystalline form of claim 1, wherein the crystalline form is formula I-form II.

13. The crystalline form of claim 1 or claim 12, characterized by an X-ray powder diffraction pattern substantially as shown in figure 6.

14. The crystalline form of any one of claims 1 or 12-13, characterized by an X-ray powder diffraction pattern comprising peaks at 9.2, 21.7, and 30.5 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

15. The crystalline form of any one of claims 1 or 12-14, characterized by an X-ray powder diffraction pattern comprising peaks at 17.4, 18.1, 19.3, 19.8, and 30.5 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

16. The crystalline form of any one of claims 1 or 12-15, characterized by an X-ray powder diffraction pattern comprising peaks at 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, and 30.5 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

17. The crystalline form of any one of claims 1 or 12-16, characterized by an X-ray powder diffraction pattern comprising peaks at 9.2, 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, 30.5, and 34.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

18. The crystalline form of any one of claims 1 or 12-17, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 9.2, 12.6, 17.4, 18.1, 19.3, 19.8, 21.7, 28.6, 30.5, and 34.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

19. The crystalline form of any of claims 1 or 12-18, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 7 when heated at a rate of 10 ℃/min.

20. The crystalline form of any one of claims 1 or 12-19, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 68 ℃ when heated at a rate of 10 ℃/min.

21. The crystalline form of any of claims 1 or 12-20, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 92 ℃ when heated at a rate of 10 ℃/min.

22. A pharmaceutically acceptable salt of a compound of formula I

23. The pharmaceutically acceptable salt of claim 22, wherein the salt is a choline salt according to formula IA,

24. a crystalline form of the pharmaceutically acceptable salt of claim 23.

25. The crystalline form of claim 24, characterized by an X-ray powder diffraction pattern substantially as shown in figure 8.

26. The crystalline form of claim 24 or claim 25, characterized by an X-ray powder diffraction pattern comprising peaks at 19.4 and 20.0 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

27. The crystalline form of claim 24 or claim 25, characterized by an X-ray powder diffraction pattern comprising peaks at 18.5, 19.4, 20.0, and 22.6 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

28. The crystalline form of claim 24 or claim 25, characterized by an X-ray powder diffraction pattern comprising peaks at 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

29. The crystalline form of claim 24 or claim 25, characterized by an X-ray powder diffraction pattern comprising peaks at 9.9, 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

30. The crystalline form of claim 24 or claim 25, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 9.9, 13.3, 18.5, 19.4, 20.0, 22.6, and 24.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

31. The crystalline form of any of claims 24 to 30, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 9 when heated at a rate of 10 ℃/min.

32. The crystalline form of any one of claims 24 to 31, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 158 ℃ when heated at a rate of 10 ℃/min.

33. The crystalline form of any one of claims 24 to 32, characterized by a thermogravimetric analysis curve substantially as shown in figure 10 when heated at a rate of 20 ℃/min.

34. The pharmaceutically acceptable salt of claim 22, wherein the salt is the benzathine salt of formula IB,

35. a crystalline form of the pharmaceutically acceptable salt of claim 34.

36. The crystalline form of claim 35, characterized by an X-ray powder diffraction pattern substantially as shown in figure 12.

37. The crystalline form of claim 35 or claim 36, characterized by an X-ray powder diffraction pattern comprising peaks at 5.8 and 18.2 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

38. The crystalline form of claim 35 or claim 36, characterized by an X-ray powder diffraction pattern comprising peaks at 5.8, 16.6, 18.2, and 20.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

39. The crystalline form of claim 35 or claim 36, characterized by an X-ray powder diffraction pattern comprising peaks at 5.8, 12.6, 16.6, 18.2, and 20.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

40. The crystalline form of claim 35 or claim 36, characterized by an X-ray powder diffraction pattern comprising peaks at 5.8, 12.6, 16.6, 18.2, 20.7, and 22.2 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

41. The crystalline form of claim 35 or claim 36, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 5.8, 12.6, 16.6, 18.2, 20.7, and 22.2 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

42. The crystalline form of any of claims 35 to 41, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 13 when heated at a rate of 10 ℃/min.

43. The crystalline form of any one of claims 35 to 42, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 112 ℃ when heated at a rate of 10 ℃/min.

44. The crystalline form of any one of claims 35 to 43, characterized by a thermogravimetric analysis curve substantially as shown in figure 14 when heated at a rate of 20 ℃/min.

45. The pharmaceutically acceptable salt of claim 22, wherein the salt is an imidazolium salt of formula IC:

46. a crystalline form of the pharmaceutically acceptable salt of claim 45.

47. The crystalline form of claim 46, characterized by an X-ray powder diffraction pattern substantially as shown in figure 16.

48. The crystalline form of claim 46 or claim 47, characterized by an X-ray powder diffraction pattern comprising peaks at 14.1 and 17.0 degrees ± 0.2 degrees 2-theta on the 2-theta scale at λ =1.54 angstroms (Cu K α).

49. The crystalline form of claim 46 or claim 47, characterized by an X-ray powder diffraction pattern comprising peaks at 14.1, 17.0, 17.9, 18.8, and 20.6 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

50. The crystalline form of claim 46 or claim 47, characterized by an X-ray powder diffraction pattern comprising peaks at 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, and 23.8 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

51. The crystalline form of claim 46 or claim 47, characterized by an X-ray powder diffraction pattern comprising peaks at 6.5, 7.0, 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, and 23.8 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

52. The crystalline form of claim 46 or claim 47, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 6.5, 7.0, 14.1, 17.0, 17.9, 18.8, 20.6, 22.0, 22.9, 23.8, 24.4, and 26.5 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

53. The crystalline form of any one of claims 46 to 52, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 17 when heated at a rate of 10 ℃/min.

54. The crystalline form of any one of claims 46 to 53, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 135 ℃ when heated at a rate of 10 ℃/min.

55. The crystalline form of any one of claims 46 to 54, characterized by a thermogravimetric analysis curve substantially as shown in figure 18 when heated at a rate of 20 ℃/min.

56. The pharmaceutically acceptable salt of claim 22, wherein the salt is a piperazine salt of formula ID,

57. a crystalline form of the pharmaceutically acceptable salt of claim 56.

58. The crystalline form of claim 57, wherein said form is crystalline form 1.

59. The crystalline form of claim 58, characterized by an X-ray powder diffraction pattern substantially as shown in figure 20.

60. The crystalline form of claim 58 or claim 59, characterized by an X-ray powder diffraction pattern comprising peaks at 7.1, 12.2, and 14.8 degrees ± 0.2 degrees 2-theta on the 2-theta scale at λ =1.54 angstroms (Cu K α).

61. The crystalline form of claim 58 or claim 59, characterized by an X-ray powder diffraction pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, 17.9, and 19.7 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

62. The crystalline form of claim 58 or claim 59, characterized by an X-ray powder diffraction pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, and 20.5 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

63. The crystalline form of claim 58 or claim 59, characterized by an X-ray powder diffraction pattern comprising peaks at 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, 20.5, and 22.8 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

64. The crystalline form of claim 58 or claim 59, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 7.1, 12.2, 14.8, 16.0, 17.9, 19.7, 20.5, and 22.8 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

65. The crystalline form of any one of claims 58 to 64, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 21 when heated at a rate of 10 ℃/min.

66. The crystalline form of any one of claims 58 to 65, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 160 ℃ when heated at a rate of 10 ℃/min.

67. The crystalline form of any one of claims 58 to 66, characterized by a thermogravimetric analysis curve substantially as shown in figure 22 when heated at a rate of 20 ℃/min.

68. The crystalline form of claim 57, wherein said form is crystalline form 2.

69. The crystalline form of claim 68, characterized by an X-ray powder diffraction pattern substantially as shown in figure 20A.

70. The crystalline form of claim 68 or claim 69, characterized by an X-ray powder diffraction pattern comprising peaks at 16.5 and 17.8 degrees ± 0.2 degrees 2-theta on the 2-theta scale at λ =1.54 angstroms (Cu K α).

71. The crystalline form of claim 68 or claim 69, characterized by an X-ray powder diffraction pattern comprising peaks at 5.5, 6.2, 8.6, 14.0, 16.5, and 17.8 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

72. The crystalline form of claim 68 or claim 69, characterized by an X-ray powder diffraction pattern comprising peaks at 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

73. The crystalline form of claim 68 or claim 69, characterized by an X-ray powder diffraction pattern comprising peaks at 5.5, 6.2, 8.6, 14.0, 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

74. The crystalline form of claim 68 or claim 69, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 5.5, 6.2, 8.6, 14.0, 16.5, 17.8, 19.1, 20.5, 22.1, and 23.0 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

75. The crystalline form of any one of claims 68 to 74, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 21A when heated at a rate of 10 ℃/min.

76. The crystalline form of any one of claims 68 to 75, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 143 ℃ when heated at a rate of 10 ℃/min.

77. The crystalline form of claim 57, wherein said form is crystalline form 3.

78. The crystalline form of claim 77, characterized by an X-ray powder diffraction pattern substantially as shown in figure 20B.

79. The crystalline form of claim 77 or claim 78, characterized by an X-ray powder diffraction pattern comprising peaks at 18.5, 19.4, and 19.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

80. The crystalline form of claim 77 or claim 78, characterized by an X-ray powder diffraction pattern comprising peaks at 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

81. The crystalline form of claim 77 or claim 78, characterized by an X-ray powder diffraction pattern comprising peaks at 13.8, 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

82. The crystalline form of claim 77 or claim 78, characterized by an X-ray powder diffraction pattern comprising peaks at 6.3, 6.7, 11.0, 11.6, 13.8, 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

83. The crystalline form of claim 77 or claim 78, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 6.3, 6.7, 11.0, 11.6, 13.8, 16.5, 16.9, 18.5, 19.4, 19.9, and 22.7 degrees ± 0.2 degrees 2 θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

84. The pharmaceutically acceptable salt of claim 22, wherein the salt is a piperidine salt of formula IE,

85. a crystalline form of the pharmaceutically acceptable salt of claim 84.

86. The crystalline form of claim 85, wherein the form is crystalline form 1.

87. The crystalline form of claim 86, characterized by an X-ray powder diffraction pattern substantially as shown in figure 24.

88. The crystalline form of claim 86 or claim 87, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3 and 17.9 degrees ± 0.2 degrees 2-theta on the 2-theta scale at λ =1.54 angstroms (Cu K α).

89. The crystalline form of claim 86 or claim 87, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 12.2, 16.1, and 17.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

90. The crystalline form of claim 86 or claim 87, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, and 19.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

91. The crystalline form of claim 86 or claim 87, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, 19.8, 20.6, and 22.9 degrees ± 0.2 degrees 2 Θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

92. The crystalline form of claim 86 or claim 87, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 7.3, 12.2, 14.3, 14.8, 16.1, 17.9, 19.8, 20.6, and 22.9 degrees ± 0.2 degrees 2 Θ on the 2 θ scale at λ =1.54 angstroms (Cu K α).

93. The crystalline form of any one of claims 86 to 92, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 25 when heated at a rate of 10 ℃/min.

94. The crystalline form of any one of claims 86 to 93, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 174 ℃ when heated at a rate of 10 ℃/min.

95. The crystalline form of any one of claims 86 to 94, characterized by a thermogravimetric analysis curve substantially as shown in figure 26 when heated at a rate of 20 ℃/min.

96. The crystalline form of claim 85, wherein the form is crystalline form 2.

97. The crystalline form of claim 96, characterized by an X-ray powder diffraction pattern substantially as shown in figure 24A.

98. The crystalline form of claim 96 or claim 97, characterized by an X-ray powder diffraction pattern comprising a peak at 18.3 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

99. The crystalline form of claim 96 or claim 97, characterized by an X-ray powder diffraction pattern comprising peaks at 10.9, 16.8, and 18.3 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

100. The crystalline form of claim 96 or claim 97, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 16.8, 18.3, and 20.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

101. The pharmaceutically acceptable salt of claim 22, wherein the salt is a potassium salt of formula IF,

102. a crystalline form of the pharmaceutically acceptable salt of claim 101.

103. The crystalline form of claim 102, characterized by an X-ray powder diffraction pattern substantially as shown in figure 28.

104. The crystalline form of claim 102 or claim 103, characterized by an X-ray powder diffraction pattern comprising peaks at 9.1, 10.4, 18.0, and 19.3 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

105. The crystalline form of claim 102 or claim 103, characterized by an X-ray powder diffraction pattern comprising peaks at 9.1, 10.4, 19.3, and 22.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

106. The crystalline form of claim 102 or claim 103, characterized by an X-ray powder diffraction pattern comprising peaks at 9.1, 10.4, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

107. The crystalline form of claim 102 or claim 103, characterized by an X-ray powder diffraction pattern comprising peaks at 9.1, 10.4, 12.5, 15.1, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

108. The crystalline form of claim 102 or claim 103, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 9.1, 10.4, 12.5, 15.1, 18.0, 19.3, 22.8, and 24.4 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

109. The crystalline form of any one of claims 102 to 108, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 29 when heated at a rate of 10 ℃/min.

110. The crystalline form of any one of claims 102 to 109, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 150 ℃ when heated at a rate of 10 ℃/min.

111. The pharmaceutically acceptable salt according to claim 22, wherein the salt is the (S) - (-) - α -methylbenzylamine salt of formula IG,

112. a crystalline form of the pharmaceutically acceptable salt of claim 111.

113. The crystalline form of claim 112, characterized by an X-ray powder diffraction pattern substantially as shown in figure 30.

114. The crystalline form of claim 112 or claim 113, characterized by an X-ray powder diffraction pattern comprising a peak at 19.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

115. The crystalline form of claim 112 or claim 113, characterized by an X-ray powder diffraction pattern comprising a peak at 18.2 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

116. The crystalline form of claim 112 or claim 113, characterized by an X-ray powder diffraction pattern comprising peaks at 18.2 and 19.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

117. The crystalline form of any one of claims 112 to 116, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 31 when heated at a rate of 10 ℃/min.

118. The crystalline form of any one of claims 112 to 117, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 75 ℃ when heated at a rate of 10 ℃/min.

119. The crystalline form of any one of claims 112 to 118, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 114 ℃ when heated at a rate of 10 ℃/min.

120. The pharmaceutically acceptable salt of claim 22, wherein the salt is the ethylenediamine salt of formula IH,

121. a crystalline form of the pharmaceutically acceptable salt of claim 120.

122. The crystalline form of claim 121, wherein said crystalline form is crystalline form 1.

123. The crystalline form of claim 122, characterized by an X-ray powder diffraction pattern substantially as shown in figure 32.

124. The crystalline form of claim 122 or claim 123, characterized by an X-ray powder diffraction pattern comprising peaks at 9.4, 10.6, 17.7, and 18.3 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

125. The crystalline form of claim 122 or claim 123, characterized by an X-ray powder diffraction pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, and 18.3 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

126. The crystalline form of claim 122 or claim 123, characterized by an X-ray powder diffraction pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, and 22.0 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

127. The crystalline form of claim 122 or claim 123, characterized by an X-ray powder diffraction pattern comprising peaks at 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, 22.0, 23.1, and 24.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

128. The crystalline form of claim 122 or claim 123, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 9.4, 10.6, 15.4, 17.7, 18.3, 19.6, 22.0, 23.1, and 24.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

129. The crystalline form of claim 121, wherein the crystalline form is crystalline form 2.

130. The crystalline form of claim 129, characterized by an X-ray powder diffraction pattern substantially as shown in figure 32A.

131. The crystalline form of claim 129 or claim 130, characterized by an X-ray powder diffraction pattern comprising a peak at 17.8 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

132. The crystalline form of claim 129 or claim 130, characterized by an X-ray powder diffraction pattern comprising peaks at 17.8, 21.8, 22.7, and 25.9 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

133. The crystalline form of claim 129 or claim 130, characterized by an X-ray powder diffraction pattern comprising peaks at 17.8, 21.8, 22.7, 25.9, and 29.5 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

134. The crystalline form of claim 129 or claim 130, characterized by an X-ray powder diffraction pattern comprising peaks at 17.8, 21.8, 22.7, 25.9, 29.5, and 35.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

135. The crystalline form of claim 129 or claim 130, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 17.8, 21.8, 22.7, 25.9, 29.5, and 35.7 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

136. The pharmaceutically acceptable salt of claim 22, wherein the salt is a 4- ((2-aminoethyl) amino) -4-methylpentan-2-one salt of formula IK,

137. a crystalline form of the pharmaceutically acceptable salt of claim 136.

138. The crystalline form of claim 137, characterized by an X-ray powder diffraction pattern substantially as shown in figure 34.

139. The crystalline form of claim 137 or claim 138, characterized by an X-ray powder diffraction pattern comprising peaks at 16.3, 17.2, and 18.0 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

140. The crystalline form of claim 137 or claim 138, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 12.2, 12.8, 16.3, and 17.2 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

141. The crystalline form of claim 137 or claim 138, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 12.2, 12.8, 16.3, 17.2, 18.0, 20.8, and 23.2 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

142. The crystalline form of claim 137 or claim 138, characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 12.2, 12.8, 16.3, 17.2, 18.0, 20.8, 23.2, 24.3, and 26.6 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

143. The crystalline form of claim 137 or claim 138, characterized by an X-ray powder diffraction pattern comprising peaks at one or more of 7.3, 12.2, 12.8, 16.3, 17.2, 18.0, 20.8, 23.2, 24.3, and 26.6 degrees ± 0.2 degrees 2 Θ on the 2 Θ scale at λ =1.54 angstroms (Cu ka).

144. The crystalline form of any one of claims 137 to 143, characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 35 when heated at a rate of 10 ℃/min.

145. The crystalline form of any one of claims 137 to 144, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 170 ℃ when heated at a rate of 10 ℃/min.

146. The crystalline form of any one of claims 137 to 145, characterized by a thermogravimetric analysis curve substantially as shown in figure 36 when heated at a rate of 20 ℃/min.

147. A pharmaceutical composition comprising a compound according to any one of claims 1 to 146 and a pharmaceutically acceptable excipient.

148. A method of inhibiting an MCL-1 enzyme, the method comprising contacting the MCL-1 enzyme with an effective amount of a compound of any one of claims 1 to 146.

149. A method of treating a disease or disorder associated with aberrant MCL-1 activity in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 146.

150. The method of claim 149, wherein the disease or disorder associated with aberrant MCL-1 activity is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

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